down syndrome literature review

• Open access
• Published: 11 June 2015

“Down syndrome: an insight of the disease”

• Ambreen Asim 1 ,
• Ashok Kumar 1 ,
• Srinivasan Muthuswamy 1 ,
• Shalu Jain 1 &
• Sarita Agarwal 1  

Journal of Biomedical Science volume  22 , Article number:  41 ( 2015 ) Cite this article

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Down syndrome (DS) is one of the commonest disorders with huge medical and social cost. DS is associated with number of phenotypes including congenital heart defects, leukemia, Alzeihmer’s disease, Hirschsprung disease etc. DS individuals are affected by these phenotypes to a variable extent thus understanding the cause of this variation is a key challenge. In the present review article, we emphasize an overview of DS, DS-associated phenotypes diagnosis and management of the disease. The genes or miRNA involved in Down syndrome associated Alzheimer’s disease, congenital heart defects (AVSD), leukemia including AMKL and ALL, hypertension and Hirschprung disease are discussed in this article. Moreover, we have also reviewed various prenatal diagnostic method from karyotyping to rapid molecular methods -  MLPA, FISH, QF-PCR, PSQ, NGS and noninvasive prenatal diagnosis in detail.

Introduction

Down syndrome is one of the most leading causes of intellectual disability and millions of these patients face various health issues including learning and memory, congenital heart diseases(CHD), Alzheimer’s diseases (AD), leukemia, cancers and Hirschprung disease(HD). The incidence of trisomy is influenced by maternal age and differs in population (between 1 in 319 and 1 in 1000 live births) [ 1 - 5 ]. DS has high genetic complexity and phenotype variability [ 6 - 8 ]. Trisomic fetuses are at elevated risk of miscarriages and DS people have increased incidence of developing several medical conditions [ 9 ]. Recent advancement in medical treatment with social support has increased the life expectancy for DS population. In developed countries, the average life span for DS population is 55 years [ 10 ].

Various conditions associated with Downs’s syndrome with its causative genes.

Human Chromosome 21

DS complex phenotype results from dosage imbalance of genes located on human chromosome 21(Hsa 21). The genetic nature of DS together with the relatively small size of Hsa 21 encouraged scientist to concentrate efforts towards the complete characterization of this chromosome in the past few years. The length of 21q is 33.5 Mb [ 11 ] and 21 p is 5–15 Mb [ 12 ]. A total 225 genes was estimated when initial sequence of 21q was published [ 11 ]. Hsa 21 has 40.06% repeat content out of which the repeat content of SINE’s, LINE’s, and LTR are 10.84%, 15.15%, 9.21% respectively. The Table  1 given below highlights some of the genes present on chromosome 21.

Features of DS

There are various conserved features occurring in all DS population, including learning disabilities, craniofacial abnormality and hypotonia in early infancy [ 13 ]. Some people of DS are affected by variant phenotypes including atrioventricular septal defects (AVSD) in heart, leukemia’s (both acute megakaryoblastic leukemia(AMKL) and acute lymphoblastic leukemia(ALL)), AD and HD. DS individual have variety of physical characteristics like a small chin, slanted eye, poor muscle tone, a flat nasal bridge, a single crease of the palm and a protuding due to small mouth and large tongue [ 14 ]. Other features includes big toe, abnormal pattern of fingerprint and short fingers.

Genetics of the disease

The most common cause of having a DS babies is presence extra copy chromosome 21 resulting in trisomy. The other causes can be Robertsonian translocation and isochromosomal or ring chromosome. Ischromosome is a term used to describe a condition in which two long arms of chromosome separate together rather than the long and short arm separating together during egg sperm development. Trisomy 21 (karyotype 47, XX, + 21 for females and 47, XY, + 21 for males) is caused by a failure of the chromosome 21 to separate during egg or sperm development. In Robertsonian translocation which occurs only in 2-4% of the cases, the long arm of the chromosome 21 is attached to another chromosome (generally chromosome 14). While mosaicism deals with the error or misdivision occurs after fertilization at some point during cell division. Due to this people with mosaic DS have two cell lineages which contribute to tissues and organs of individuals with Mosacism (one with the normal number of chromosomes, and other one with an extra number 21) [ 15 ].

Genotype-phenotype correlation

Gene dosage imbalance hypothesis states that DS patients have an increased dosage or copy number of genes on Hsa 21 that may lead to an increase in gene expression [ 13 - 15 ]. This hypothesis has been extended to include the possibility that specific genes or subsets of genes may control specific DS phenotypes [ 16 ]. Amplified developmental instability hypothesis states that a non-specific dosage of a number of trisomic genes leads to a genetic imbalance that causes a great impact on the expression and regulation of many genes throughout the genome [ 13 , 14 ]. Another hypothesis known as critical region hypothesis was also added to this list. Phenotypic analyses was done on individuals with partial trisomy for Hsa21 identified that only one or a few small chromosomal regions, termed “Down syndrome critical regions” (DSCR) a region of 3.8-6.5 Mb on 21q21.22, with approximately 30 genes responsible for the majority of DS phenotypes [ 15 , 16 ]. Previously a region of 1.6 to 2.5 Mb was recognised as sufficient cause for DS pehnotype [17, 18]. The sequencing of Hsa 21 proved to be an important factor in the progression of DS research [ 19 ] and led to further insight into genotype-phenotype correlations associated with DS and precise characterizations of DSCR regions [ 13 ]. A “critical region” within 21q22 was believed to be responsible for several DS phenotypes including craniofacial abnormalities, congenital heart defects of the endocardial cushions, clinodactyly of the fifth finger and mental retardation [ 20 ].

Dual-specificity tyrosine phosphorylation-regulated kinase (DYRK1A) and regulator of calcineurin 1 (RCAN1), Down syndrome cell adhesion molecule (DSCAM) has been suggested to play a critical role in the developing brain and has also been identified as a candidate gene for the increased risk of CHD in DS individuals [ 21 , 22 ]. DSCAM is a critical factor in neural differentiation, axon guidance, and the establishment of neural networks and it has been suggested that the disruption of these processes contributes to the DS neurocognitive phenotype [ 22 ]. Based on thorough analyses of studies on humans and DS mouse models, it is evident that there is not a single critical region of genes sufficient to cause all DS phenotypes. Alternatively, it is likely that there are multiple critical regions or critical genes contributing to a respective phenotype or group of phenotypes associated with DS [ 23 ].

Various clinical conditions associated to Down syndrome

The various clinical conditions associated with DS are Alzheimer’s disease, heart defects, leukemia, hypertension and gastrointestinal problems (Figure 1 ). The molecular pathogenesis mechanism of these DS related phenotype must be studied along with its causative agents in order to have a better understanding of the disease. Below are some DS related phenotype discussed in detail which are as follows:

Neurological problems

DS patients have greatly increased risk of early onset AD. After the age of 50, the risk of developing dementia increases in DS patients up to 70% [ 23 - 27 ]. There are various genes reported to cause early onset AD. Some of the genes described in the current literature are APP (amyloid precursor protein), BACE2 (beta secretase 2), PICALM (Phosphatidylinositol binding clathrin assembly protein) and APOE(Apolipoprotein E) etc. APP is an integral membrane protein which is concentrated in synapse of neurons and trisomy of this protein is likely to make significant contribution to the increased frequency of dementia in DS individuals. The triplication of Hsa 21 along with APP in people without DS has been recently shown to be associated with early onset AD. A tetranucleotide repeat, ATTT , in intron 7 of the amyloid precursor protein has been associated with the age of onset of AD in DS in a preliminary study [ 28 ]. Various mouse models are used to observe degeneration of basal forebrain cholinergic neurons (BFCNs). Ts65Dn mice is dependent on trisomy of APP expression of retrograde axonal transport [ 29 ]. Studies have also revealed that BACE2 which encodes enzyme beta secretase 2 is also involved in AD. APP and BACE 2 genes are located on chromosome 21. The current data on DS support the association of haplotypes in BACE2 with AD [ 30 ]. Besides APP and BACE2 genes, other genes like PICALM and APOE are also found to be associated with the age of onset of Alzheimer’s dimentia in DS [ 31 ].

Cardiac problems

The incidence of CHD in newborn babies with DS is up to 50% [ 32 ]. Endocardial cushion defect also called as atrioventricular cushion defect is most common form which affects up to 40% of the patients. Ventricular septal defect (VSD) is also present in these population which affects up to 35% of the patients [ 33 ]. The essential morphological hallmark of an AVSD is the presence of a common atrioventricular junction as compared to the separate right and left atrioventricular junction in the normal heart. Other morphological features include defects of the muscular and membranous atrioventricular septum and an ovoid shape of the common atrioventricular junction. There is disproportion of outlet and inlet dimensions of the left ventricle, with the former greater than the latter as compared to the normal heart where both dimensions are similar [ 34 ]. While in case of VSD, the defect lies in ventricular septum of the heart due to which some of the blood from the left ventricle leaks into the right ventric leading to pulmonary hypertension. Mutation in non Hsa 21 CRELD1 (Cysteine rich EGF like domain1) gene contributes to the development of AVSD in DS [ 35 ]. CRELD1 is located on chromosome 3p25. It encodes a cell surface protein that functions as cell adhesion molecule and is expressed during cardiac cushion development. CRELD1 gene contains 11 exons spanning approximately 12 kb [ 36 ]. To the present, two specific genetic loci for AVSD have been identified. One was AVSD 1 locus present on chromosome 1p31-p21 [ 37 ]. Other locus was present on chromosome 3p25 and the corresponding gene was CRELD1 [ 36 , 38 ]. Maslen et al . in [ 33 ] have identified two heterozygous missense mutation (p.R329C and p.E414K) with two subjects in DS and AVSD. They have recruited 39 individual of DS with complete AVSD and have found the same mutations. In the same study, DNA of 30 individual of trisomy without CHD was studied for both mutations, no such mutation was identified [ 35 ]. R329C which was originally reported in an individual with sporadic partial AVSD and now it is also detected in individual of DS with AVSD. Interestingly, with the same mutation (p.R329C), the severity of heart defect was greater in patients of DS with AVSD. Thus, identification of CRELD 1 mutation in 2/39 individual (5.1%) of DS with complete AVSD suggests the defects in CRELD 1 contribute to pathogenesis of AVSD in context with trisomy 21.

Hematological problems

Patients with DS display a unique spectrum of malignancies, which include leukemia’s as well as solid tumors. The first report of leukemia in a DS patient occurred in 1930 [ 39 ] and the first systematic study in 1957 [ 40 ]. Studies indicate that patients with DS have a 10–20 fold increased relative risk of leukemia, with a cumulative risk of 2% by age 5 and 2.7% by age 30 [ 41 ]. They constitute approximately 2% of all pediatric acute lymphoblastic leukemia(ALL) and approximately 10% of pediatric acute myeloid leukemia (AML). Leukemogenesis of acute megakaryoblastic leukemia (AMKL) in DS patients is associated with the presence of somatic mutations involving GATA 1 gene (or also called as GATA-binding factor 1) [ 42 ]. GATA 1 is a chromosome X- linked transcription factor which is essential for erythoid and megakaryocytic differentiation. Because of these GATA 1 mutations, there is a production of shorter GATA 1 protein thereby leading to uncontrolled proliferation of immature megakaryocytes [ 42 , 43 ]. On the other hand, acquired gain of function mutation in Janus Kinase 2 gene are present in approximately 30% of cases with ALL in DS [ 44 , 45 ].

Hypertension

People with DS have been reported to have a reduced incidence of hypertension [ 46 , 47 ]. Trisomy of the Hsa21 microRNA hsa-miR-155 contributes to this [ 48 ]. Hsa-miR-155 is proposed to specifically target one allele of the type-1 angiotensin II receptor (AGTR1) gene, resulting in it’s under- expression, which contribute to a reduced risk of hypertension. Further studies are required to validate this hypothesis and determine whether other genes may also protect people with DS against hypertension.

Gastrointestinal problems

DS patients constitute ~12% of all cases of HD. Duodenal stenosis (DST) and imperforate anus (IA) are 260 and 33 times more likely to occur DS [ 23 , 49 ]. HD is a form of low intestinal obstruction caused by the absence of normal myenteric ganglion cells in a segment of the colon [ 50 ]. In HD children, the absence of ganglion cells results in the failure of the distal intestine to relax normally. Peristaltic waves do not pass through the aganglionic segment and there is no normal defecation, leading to functional obstruction. Abdominal distention, failure to pass meconium, enterocolitis and bilious vomiting are the predominant signs and symptoms and appear within a few days after birth. Infants with duodenal atresia or DST present with bilious vomiting early in the neonatal period. If left untreated, it will result in severe dehydration and electrolyte imbalance. IA is a birth defects in which the rectum is malformed and it is associated with an increased incidence of some other specific anomalies as well, together being called the VACTERL association: vertebral anomalies, anal atresia, cardiovascular anomalies, tracheoesophageal fistula, esophageal atresia, renal and limb defects.

Alterations of approximately 10 non Hsa21 genes have been linked to this disease [ 51 ]. Several researches have shown that HD contain the DSCAM gene which is expressed in neural crest that give rise to enteric nervous system [ 49 ]. Overlapping critical region was described both for DST and IA [ 51 ]. No other Hsa21 genes have been implicated so far.

Diagnostic methods

Prevention of DS depends upon offering prenatal diagnosis to high risk pregnancies via amniocentesis and chorionic villus sampling (CVS). Amniocentesis and CVS are quite reliable but offers risk of miscarriage of between 0.5 to 1% [ 52 ]. Based soft markers like small or no nasal bone, large ventricles and nuchal fold thickness, the risk of DS for fetus can be identified through ultrasound generally at 14 to 24 weeks of gestation [ 53 ]. Increased fetal nuchal translucency indicates an increased risk of DS [ 54 ]. The other methods used for prenatal diagnosis in which traditional cytogenic analysis is still widely used in different countries. However some rapid molecular assays-FISH(fluorescent in situ hybridization), QF-PCR (quantitative fluorescence PCR), and MLPA(multiplex probe ligation assay)- also used for prenatal diagnosis.

Routine karyotyping

Cytogenetic analysis of metaphase karyotype remains the standard practice to identify not only trisomy 21, but also all other aneuploidies and balanced translocations. Details on diagnostic methods with advantages and disadvantages are mentioned in Table  2 .

Rapid aneuploidy testing methods

Over the past 10 years however, several other methods have been developed and used for the rapid detection of trisomy 21, either in fetal life or after birth. The most widely used is FISH of interphase nuclei, using Hsa 21-specific probes or whole-Hsa 21 [ 55 ]. An alternative method that is now widely used in some countries is QF-PCR, in which DNA polymorphic markers (microsatellites) on Hsa 21 are used to determine the presence of three different alleles [ 56 ]. This method relies on informative markers and the availability of DNA. Rapid diagnosis by PCR-based methods using polymorphic STR markers may reduce these difficulties using conventional approach. Using STR markers method we can detect trisomy in 86.67% cases with only two markers. Using more number of markers can further increase the reliability of the test. Simultaneously parental origin of the nondysjunction can also be detected [ 57 , 58 ]. Additional method to measure copy number of DNA sequences include MLPA [ 59 ] which was first introduced in 2002 as a method of relative quantification in DNA. MLPA offers various advantages like – a very short time for diagnosis (2–4 days), effectiveness, simplicity and relatively low costs. It is based on hybridization and PCR method and is divided into four steps: DNA denaturation, hybridization of probe to the complementary target sequence, probe ligation and PCR amplification. And finally capillary electrophoresis of PCR amplified products is carried out. However MLPA is unable to exclude low level placental and true mosaicism [ 60 ].

Advancement in the diagnosis

A recent method, termed paralogous sequence quantification (PSQ), uses paralogous sequences to quantify the Hsa 21 copy number. PSQ is a PCR based method for the detection of targeted chromosome number abnormalities termed paralogous sequence quantification (PSQ), based on the use of paralogous genes. Paralogous sequences have a high degree of sequence identity, but accumulate nucleotide substitutions in a locus specific manner. These sequence differences, which are termed as paralogous sequence mismatches (PSMs), can be quantified using pyrosequencing technology, to estimate the relative dosage between different chromosomes. PSQ is a robust, easy to interpret, and easy to set up method for the diagnosis of common aneuploidies, and can be performed in less than 48 h, representing a competitive alternative for widespread use in diagnostic laboratories. The sequencing is quantitatively done by using pyrosequencing [ 61 ]. Finally, comparative genomic hybridization (CGH) on BAC chips can be used for the diagnosis of full trisomy or monosomy, and for partial (segmental) aneuploidies [ 62 , 63 ].

Noninvasive Prenatal diagnosis

Fetal cells in maternal ciruculation: Ever since the discovery of presence of fetal lymphocytes in maternal blood was made in 1969, the investigators are trying to develop genetics-based noninvasive prenatal diagnostics (NIPD) [ 64 ]. Despite several advantages offered by this approach, the use of fetal cells for NIPD has never reached clinical implementation because of their paucity (on the order of a few cells per milliliter of maternal blood) and concerns of fetal cell persistence in the maternal circulation between pregnancies.

Cell free fetal DNA from maternal serum: This novel approach was proposed in 1997. Cell-free fetal DNA constitutes between 5% and 10% of the total DNA in maternal plasma and increases during gestation and rapidly clears from the circulation post delivery. Several clinical applications based on the analysis of cell-free fetal DNA have been developed like determining fetal Rh D status in Rh D-negative women [ 65 ], sex in sex-linked disorders [ 66 , 67 ], and detection of paternally inherited autosomal recessive and dominant mutations [ 68 ]. However, there remains the outstanding challenge of the use of cell-free fetal DNA for the detection of chromosomal aneuploidy, in particular trisomies 21, 18, and 13. Several approaches have been adopted like the origin of circulating cell-free fetal DNA is primarily the placenta, whereas maternal cell-free DNA is derived from maternal leukocytes [ 69 ]. The approach includes studying differences in genomic DNA methylation between the placenta and paired maternal leukocytes, investigators have characterized placenta-specific epigenetic markers [ 70 ] and also finding of circulating cell-free placenta-derived mRNA allowed the identification of placenta-specific mRNA production [ 71 ].

The concept of digital PCR was also introduced to serve the same purpose. In digital PCR, individual fetal and maternal circulating cell-free DNA fragments are amplified under limiting-dilution conditions and the total number of chromosome 21 amplifications (representing maternal plus fetal contributions) divided by the number of reference chromosome amplifications should yield a ratio indicating an over- or underrepresentation of chromosome 21.

Although the digital PCR approach is conceptually solid, the low percentage of cell-free fetal DNA in the maternal plasma sample requires the performance of thousands of PCRs to generate a ratio with statistical confidence. This can be overcome by using of multiple target amplifications and enrichment of cell-free fetal DNA which are still under research trail.

Next recent method added to the list is next generation sequencing (NGS) which is based on the principle of clonally amplified DNA templates (or, most recently, single DNA molecules) are sequenced in a massively parallel fashion within a flow cell [ 72 , 73 ]. NGS provides digital quantitative information, in which each sequence read is a countable “sequence tag” representing an individual clonal DNA template or a single DNA molecule. This quantification allows NGS to expand the digital PCR concept of counting cell-free DNA molecules.

Fan et al. and Chiu et al. in 2008 described noninvasive detection of trisomy 21 by NGS [ 74 ]. Both groups extracted cell-free DNA from maternal plasma samples from both euploid and trisomy pregnancies. DNA from each sample was sequenced on the Illumina Genome Analyzer, and each sequence read was aligned to the reference human genome. Chiu et al. build on their earlier work with the Illumina Genome Analyzer and demonstrate noninvasive NGS-based trisomy 21 detection with the sequencing-by-ligation approach on the Life Technologies SOLiD platform [ 75 ]. Cell-free DNA was extracted from 15 pregnant women, 5 of whom carried trisomy 21 fetuses and it was clonally amplified by emulsion PCR, and sequenced in 1 chamber of an 8-chamber SOLiD slide. This process yielded a median of 59 × 10 6 50-base reads per sample. A median of 12 × 10 6 reads (or 21%) were each aligned uniquely to one location of the reference human genome (with masking of repeat regions), for a coverage of approximately 20% of the haploid human genome. For each trisomy 21 case, the chromosome 21 z score value indicated a 99% chance of a statistically significant difference from the chromosome 21 z scores for the controls. As reported earlier with the Illumina Genome Analyzer, a nonuniform distribution of aligned sequence reads was observed with the SOLiD data.

The current time for sample processing, sequencing, and data interpretation in experienced hands is 5 to 8 days for the Genome Analyzer and SOLiD platforms respectively with the cost of approximately $700 – $1000 per sample. Going forward, one can expect streamlining and automation of technical processes and data analysis, coupled with reduced sequencing costs.

Ultimately, reduced sequencing costs and turnaround times could pave the way for NGS-based NIPD to be considered as an alternative to serum biomarker screening, which,while cost-effective remains prone to false positives. Forty years after the discovery of circulating fetal cells, the vision of NIPD appears clearer and closer.

Management of the disease

One of the hallmarks of DS is the variability in the way that the condition affects people with DS. With the third 21st chromosome existing in every cell, it is not surprising to find that every system in the body is affected in some way. However, not every child with DS has the same problems or associated conditions. Parents of children with DS should be aware of these possible conditions so they can be diagnosed and treated quickly and appropriately. The goal of the study is to point out the most common problems of which parents should be aware.

Timely surgical treatment of cardiac defects during first 6 months of life may prevent from serious complications. Congenital cataracts occur in about 3% of children and must be extracted soon after birth to allow light to reach the retina. A balance diet and regular exercise are needed to maintain appropriate weight. Feeding problems and failure to thrive usually improve after cardiac surgery. A DS child should have regular check up from various consultants. These include:

Clinical geneticist - Referral to a genetics counseling program is highly desirable

Developmental pediatrician

Cardiologist - Early cardiologic evaluation is crucial for diagnosing and treating congenital heart defects, which occur in as many as 60% of these patients

Pediatric pneumonologist -Recurrent respiratory tract infections are common in patients with DS

Ophthalmologist

Neurologist/Neurosurgeon – As many as 10% of patients with DS have epilepsy; therefore, neurologic evaluation may be needed

Orthopedic specialist

Child psychiatrist - A child psychiatrist should lead liaison interventions, family therapies, and psychometric evaluations

Physical and occupational therapist

Speech-language pathologist

Audiologist

DS or Trisomy 21, being the most common chromosomal abnormality among live born infants, is associated with a number of congenital malformations. Several theories have been put forward to increase our understanding in phenotype and genotype correlation. A “critical region” within 21q22 was believed to be responsible for several DS phenotypes including craniofacial abnormalities, congenital heart defects of the endocardial cushions, clinodactyly of the fifth finger and mental retardation and several other features. The primary goal of this review is to unravel the common genes involved in DS associated phenotypes, including APP, BACE2, PICALM, APOE, GATA 1, JAK 2, CRELD 1 and DSCAM. This reviews also provides the detailed description on the application of techniques to prenatal diagnosis in DS. Rapid aneuploidy testing has been introduced in mid 1990’s in the form of FISH where testing can be done on uncultured amniocytes. Within a couple of years, MLPA and QF-PCR has been added in the list of rapid aneuploidy testing. The other methods includes: NGS for cell free fetal DNA screening for maternal plasma. Except ,FISH, MLPA and QF-PCR other method are not commercialized for aneuploidy diagnosis due to their running cost, labor intensive protocol and complex data analysis. Since various clinical conditions are associated with DS, hence the management of these patients requires an organized multidisciplinary approach and continuous monitoring of these patients which has been discussed in this review article.

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Asim, A., Kumar, A., Muthuswamy, S. et al. “Down syndrome: an insight of the disease”. J Biomed Sci 22 , 41 (2015). https://doi.org/10.1186/s12929-015-0138-y

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Down syndrome (DS) is one of the most well-recognized genetic disorders. Persons with DS are known to have a variety of co-morbid medical problems, affecting nearly all organ systems. Improved healthcare interventions and research have allowed for increased life span of persons with DS, although disorders of the neurologic system remain underexplored. The purpose of this systematic review is to provide clinically pertinent information on the neurological phenotypes of frequently occurring or clinically relevant conditions. A retrospective review of MEDLINE, Scopus, and Pubmed were used to identify sources among seventeen, clinically relevant, search categories. MeSH terms all contained the phrase “Down Syndrome” in conjunction with the topic of interest. ‘Frequently-occurring’ was defined as prevalent in more than 10% of persons with DS across their lifespan, whereas ‘clinically-relevant’ was defined as a disease condition where early diagnosis or intervention can augment the disease course. In total, 4896 sources were identified with 159 sources meeting criteria for inclusion. Seventeen clinical conditions were grouped under the following subjects: hypotonia, intellectual and learning disability, cervical instability, autism spectrum disorder, epilepsy, cerebrovascular disease, Alzheimer’s disease and neuropsychiatric disease. The results of this review provide a blueprint for the clinical neurologist taking care of persons with DS across the age spectrum and indicate that there are many underrecognized and misdiagnosed co-occurring conditions in DS, highlighting the need for further research.

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Santoro, J.D., Pagarkar, D., Chu, D.T. et al. Neurologic complications of Down syndrome: a systematic review. J Neurol 268 , 4495–4509 (2021). https://doi.org/10.1007/s00415-020-10179-w

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Received : 11 August 2020

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Published : 12 September 2020

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DOI : https://doi.org/10.1007/s00415-020-10179-w

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• Published: 06 February 2020

Down syndrome

• Stylianos E. Antonarakis 1 ,
• Brian G. Skotko 2 , 3 ,
• Michael S. Rafii 4 ,
• Andre Strydom 5 ,
• Sarah E. Pape 5 ,
• Diana W. Bianchi 6 , 7 ,
• Stephanie L. Sherman 8 &
• Roger H. Reeves 9 , 10  

Nature Reviews Disease Primers volume  6 , Article number:  9 ( 2020 ) Cite this article

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• Molecular medicine

Trisomy 21, the presence of a supernumerary chromosome 21, results in a collection of clinical features commonly known as Down syndrome (DS). DS is among the most genetically complex of the conditions that are compatible with human survival post-term, and the most frequent survivable autosomal aneuploidy. Mouse models of DS, involving trisomy of all or part of human chromosome 21 or orthologous mouse genomic regions, are providing valuable insights into the contribution of triplicated genes or groups of genes to the many clinical manifestations in DS. This endeavour is challenging, as there are >200 protein-coding genes on chromosome 21 and they can have direct and indirect effects on homeostasis in cells, tissues, organs and systems. Although this complexity poses formidable challenges to understanding the underlying molecular basis for each of the many clinical features of DS, it also provides opportunities for improving understanding of genetic mechanisms underlying the development and function of many cell types, tissues, organs and systems. Since the first description of trisomy 21, we have learned much about intellectual disability and genetic risk factors for congenital heart disease. The lower occurrence of solid tumours in individuals with DS supports the identification of chromosome 21 genes that protect against cancer when overexpressed. The universal occurrence of the histopathology of Alzheimer disease and the high prevalence of dementia in DS are providing insights into the pathology and treatment of Alzheimer disease. Clinical trials to ameliorate intellectual disability in DS signal a new era in which therapeutic interventions based on knowledge of the molecular pathophysiology of DS can now be explored; these efforts provide reasonable hope for the future.

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Acknowledgements

The authors thank the members of the London Down Syndrome (LonDownS) Consortium, G. de Graaf of the Dutch Down Syndrome Foundation and F. Buckley of Down Syndrome Education International for their review of the epidemiology section of this article. Work in the authors’ laboratories and clinics was supported by grants from the SNF, EU, ERC, Jerome Lejeune, and ChildCare Foundations to S.E.A.; a Wellcome Trust Strategic Award (grant number 098330/Z/12/Z) conferred upon the LonDownS Consortium, an MRC project grant (LonDownsPREVENT MR/S011277/1), and grants from the EU Joint Programme - Neurodegenerative Disease Research (MR/R024901/1, as part of the HEROES consortium), Network of Centres of Excellence in Neurodegeneration (COEN) (MR/S005145/1), Lumind Foundation and Jerome Lejeune Foundation to A.S.; the Jerome Lejeune Foundation USA, Anna and John Sie Foundation, US National Institutes of Health (NIH; HD42053-10, UL1TR001064, ZIA HG200399-04) to D.W.B.; NIH and Lumind Foundation to S.L.S.; HD038384-20, HD098540 and the Lumind Foundation to R.H.R.; and the Alzheimer’s Society and BRC to S.P. The authors thank all past and present members of their laboratories, their collaborators and the patients and their families for their inspiration and support.

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Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland

Stylianos E. Antonarakis

Down Syndrome Program, Division of Medical Genetics, Department of Pediatrics, Massachusetts General Hospital, Boston, MA, USA

Brian G. Skotko

Department of Pediatrics, Harvard Medical School, Boston, MA, USA

Keck School of Medicine of University of Southern California, California, CA, USA

Michael S. Rafii

Department of Forensic and Neurodevelopmental Sciences, Institute of Psychiatry, Psychology & Neuroscience, King’s College London, London, UK

Andre Strydom & Sarah E. Pape

Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA

Diana W. Bianchi

National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA

Department of Human Genetics, Emory University School of Medicine, Atlanta, GA, USA

Stephanie L. Sherman

Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, MD, USA

Roger H. Reeves

McKusick-Nathans Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA

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Contributions

Introduction (S.E.A.); Epidemiology (B.G.S.); Mechanisms/pathophysiology (S.E.A., M.S.R., S.L.S. and R.H.R.); Diagnosis, screening and prevention (S.E.A. and D.W.B.); Management (A.S. and S.E.P.); Quality of life (A.S. and S.E.P.); Outlook (S.E.A.).

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Correspondence to Stylianos E. Antonarakis .

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S.E.A. is the co-founder and CEO of MediGenome, a clinical and laboratory diagnostic company. B.G.S. occasionally consults on the topic of Down syndrome through Gerson Lehrman Group. B.G.S. receives remuneration from Down syndrome non-profit organizations for speaking engagements and associated travel expenses. B.G.S. receives annual royalties from Woodbine House, Inc., for the publication of his book, Fasten Your Seatbelt: A Crash Course on Down Syndrome for Brothers and Sisters . Within the past 2 years, B.G.S. has received research funding from F. Hoffmann-La Roche, Inc., and LuMind IDSC Down Syndrome Foundation to conduct clinical trials for people with Down syndrome. B.G.S. is occasionally asked to serve as an expert witness in legal cases where Down syndrome is discussed. B.G.S. serves in a non-paid capacity on the Honorary Board of Directors for the Massachusetts Down Syndrome Congress and the Professional Advisory Committee for the National Center for Prenatal and Postnatal Down Syndrome Resources. B.G.S. has a sister with Down syndrome. M.S.R. is a consultant to AC Immune SA. A.S. has consulted for Roche Pharmaceuticals, ONO Pharma, Aelis Farma and AC Immune, and he serves on the Scientific Advisory Board of ProMIS Neurosciences. A.S. and S.E.P. provide clinical services within the UK National Health Service to individuals with Down syndrome. The remaining authors declare no competing interests.

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Down’s Syndrome Association and the Down Syndrome Medical Interest Group fact sheet: http://www.perinatalservicesbc.ca/Documents/Guidelines-Standards/Maternal/DownSyndromePracticeResource.pdf

Protein-coding genes on HSA21: https://www.ensembl.org/Homo_sapiens/Location/Chromosome?r=21

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Antonarakis, S.E., Skotko, B.G., Rafii, M.S. et al. Down syndrome. Nat Rev Dis Primers 6 , 9 (2020). https://doi.org/10.1038/s41572-019-0143-7

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DOI : https://doi.org/10.1038/s41572-019-0143-7

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Language Intervention in Down Syndrome: A Systematic Literature Review

Affiliations.

• 1 Facultad de Ciencias de la Salud, Universidad de Castilla-La Mancha, 45600 Talavera de la Reina, Spain.
• 2 Facultad de Educación de Toledo, Universidad de Castilla-La Mancha, 45005 Toledo, Spain.
• PMID: 35627579
• PMCID: PMC9140510
• DOI: 10.3390/ijerph19106043

Language is one of the most affected areas in people with Down syndrome and is one of the most influential throughout their development. That is why the linguistic difficulties presented by this group are susceptible to treatment through different specific interventions. However, little emphasis has been placed on the effectiveness and importance of this type of intervention in improving their language skills. Therefore, this work aimed to carry out a systemic literature review of language intervention programs that have been carried out in the last 20 years. To this end, a total of 18 articles were analyzed in which the effectiveness of different types of treatment related to oral language, written language and communication, in general, was studied, using the guidelines of the PRISMA Statement and the COSMIN methodology. The results highlight that language intervention improves linguistic levels in people with Down Syndrome. Most of the research focuses on early interventions and interventions carried out through individual sessions. Nevertheless, the data are unanimous in considering the efficacy and effectiveness of the proposed treatments for improving the language skills of people with Down syndrome. Thus, linguistic intervention is a fundamental area of work throughout the lives of people with Down syndrome.

Keywords: Down syndrome; intervention; language; systematic review.

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Conflict of interest statement

The authors declare no conflict of interest.

Flowchart of the information obtained…

Flowchart of the information obtained through the different phases of the systematic review.

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Language intervention in down syndrome: a systematic literature review.

1. Introduction

2. materials and methods, 2.1. strategy for the identification of articles, 2.2. strategy for the selection of articles, 2.3. strategy for the analysis of scientific evidence, 4. discussion, 5. conclusions, author contributions, institutional review board statement, informed consent statement, data availability statement, conflicts of interest.

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Moraleda-Sepúlveda, E.; López-Resa, P.; Pulido-García, N.; Delgado-Matute, S.; Simón-Medina, N. Language Intervention in Down Syndrome: A Systematic Literature Review. Int. J. Environ. Res. Public Health 2022 , 19 , 6043. https://doi.org/10.3390/ijerph19106043

Moraleda-Sepúlveda E, López-Resa P, Pulido-García N, Delgado-Matute S, Simón-Medina N. Language Intervention in Down Syndrome: A Systematic Literature Review. International Journal of Environmental Research and Public Health . 2022; 19(10):6043. https://doi.org/10.3390/ijerph19106043

Moraleda-Sepúlveda, Esther, Patricia López-Resa, Noelia Pulido-García, Soraya Delgado-Matute, and Natalia Simón-Medina. 2022. "Language Intervention in Down Syndrome: A Systematic Literature Review" International Journal of Environmental Research and Public Health 19, no. 10: 6043. https://doi.org/10.3390/ijerph19106043

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• DOI: 10.52711/2454-2652.2021.00075
• Corpus ID: 236229626

Down Syndrome: A Literature Review

• B. Maske Rutika
• Published in International Journal of… 1 July 2021

5 References

Health supervision for children with down syndrome, the incidence patterns of down syndrome in qatar, hirschsprung disease, associated syndromes and genetics: a review, increased app expression in a mouse model of down's syndrome disrupts ngf transport and causes cholinergic neuron degeneration, “down syndrome: an insight of the disease”, related papers.

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• Open access
• Published: 06 January 2021

Congenital heart disease in Down syndrome – A review of temporal changes

• Stephanie L. Santoro   ORCID: orcid.org/0000-0002-4172-0288 1 , 2 &
• Ellen Hollands Steffensen 3 , 4  

Journal of Congenital Cardiology volume  5 , Article number:  1 ( 2021 ) Cite this article

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Congenital heart disease (CHD) is a well-known co-occurring condition in Down syndrome (DS). We aimed to review the literature to evaluate the current evidence to address key questions.

A series of key questions were formulated a priori to inform the search strategy and review process. These addressed the topics of prevalence, type of CHD, severity, and screening. Using the National Library of Medicine database, PubMed, detailed literature searches were performed. The quality of available evidence was then evaluated, the existing literature was summarized, and knowledge gaps were identified.

Fifty-six relevant original articles were identified which addressed at least one key question. Study details, including: research design, internal validity, external validity, and relevant results are presented. The total prevalence of CHD reported in DS ranged from 20 to 57.9%. In later decades, the prevalence remained constant at 40—55%. The types and classification of CHD varied considerably between studies. Some studies indicate a trend towards a milder phenotype, but this was not consistent. Over time, some studies observed an improved prognosis for CHD in DS. Studies investigating screening for CHD by physical examination, chest X-ray, and electrocardiogram report sensitivities of 71–95%.

To further improve knowledge on CHD in DS, we suggest that future studies cover a wide range of nations and regions, with a longitudinal design, and account for potential confounding factors.

Introduction

Down syndrome (DS) is present in one in 800 infants born in the United States, making it the most common chromosomal condition associated with a unique medical and developmental profile [ 1 , 2 ]. Congenital heart disease (CHD) is one of the co-occurring medical diagnoses associated with DS [ 3 , 4 ]. Among patients with DS, the presence of CHD is a known contributor to morbidity and mortality [ 5 ].

Although the association of CHD with DS has been known for decades, much has changed over time in terms of available diagnostics, medical care, and treatments. We conducted this project to present an updated literature review on CHD in DS. The overarching goals of this review were to: 1) Formulate key questions a priori and identify which original articles address these key questions. 2) Search PubMed to identify original research articles that address the cardiac phenotype of individuals with DS. 3) Assess these articles using United States Preventative Services Task Force (USPTF) methods [ 6 ]. 4) Summarize the published literature and identify gaps in evidence.

Key questions

In accordance with USPSTF practice we formulated a series of key questions as outlined in a prior review [ 7 ]. By consensus, the following key questions were formulated by the authors:

What is the total prevalence of congenital heart disease in DS? And, has the prevalence of congenital heart disease in DS changed over time?

What is the type of congenital heart disease in DS? And, has the type of congenital heart disease in DS changed over time?

What is the severity of congenital heart disease in DS in terms of treatment and prognosis? And, has the severity of congenital heart disease in DS changed over time?

What screening for congenital heart disease in DS is performed in studies? And, has the screening for congenital heart disease in DS changed in the published literature over time?

PubMed literature search

Literature searches were conducted in August – September 2020 using the National Library of Medicine (NLM) biomedical literature database PubMed (MEDLINE) (NCBI 1946–2020) to identify original research manuscripts addressing our prioritized topics. We used the Medical Subject Headings (MeSH) (the NLM controlled vocabulary thesaurus for indexing) to capture related entry terminology in our searches. For example, the MeSH term “Down syndrome” included the search entry terms: Downs syndrome, Down’s syndrome, Mongolism, Trisomy 21, Partial Trisomy 21. The MeSH term “Down syndrome” was combined using the Boolean operator ‘AND’ with the MeSH term “congenital heart defect” which included the search entry terms of specific cardiac malformations, to capture the unfiltered literature. Then, the limiters “Human”, “English” were applied to narrow the scope of the search to filtered literature. We did not use subject age as a limiter. We also did not exclude articles based on timing of study either prenatal or postnatal, and did not filter our search to only live births. Abstracts were reviewed and included according to their relevance to key questions. Whenever an abstract made mention of any key question (or there was doubt) the full article was procured. The methods and results sections were then reviewed to determine which articles met inclusion or exclusion criteria. A single reviewer conducted the literature searches, reviewed articles for inclusion, and extracted data. Article inclusion criteria included: data addresses at minimum one key question and supporting data is original (not previously published). Exclusion criteria included: data does not address at least one key question, study uses an uninterpretable methodology, case series < 5, does not provide supporting data, did not present data specific to DS, focused on a single type of CHD, is a unique subset of DS (e.g. surgical patients) which would not generalize to answer our key questions.

Using only the PubMed articles meeting inclusion, data pertaining to key questions were extracted from the abstract, methods, and results sections and entered into a preformatted Excel data template for analysis. For graphical representation of temporal changes, we grouped reported CHD’s according to [ 15 ]. to facilitate comparisons across studies [ 8 ]. See Fig.  1 for an overview of the identification, inclusion and exclusion process and Supplemental Table for details of extracted data.

PRISMA Diagram of Articles Identified, Screened, Eligible, and Included in Review of CHD Phenotype in Down Syndrome. Research design hierarchy in accordance with United States Preventative Services Task Force methods

Factors which may impact these key questions such as: publication year, population details (number of subjects studied, age of sample, location, source of subjects and demographics: gender, race, prenatal or postnatal diagnosis of CHD, prenatal or postnatal diagnosis of DS) if provided, and research methodology were recorded.

Evidence ratings by condition

Included articles were critically appraised by a single reviewer to determine each study’s research design, subject ascertainment, total number of subjects, source of control subjects, and the extent of internal validity and external validity. The evaluation of internal validity considers study design factors such as ascertainment and selection bias, test procedures and consideration of confounding variables. For example, the internal validity of a cohort study is rated as good if it “Meets all criteria: comparable groups are assembled initially and maintained throughout the study (follow-up greater than or equal to 80%); reliable and valid measurement instruments are used and applied equally to all groups; interventions are spelled out clearly; all important outcomes are considered; and appropriate attention to confounders in analysis. In addition, intention-to-treat analysis is used for RCTs” (USPSTF Procedure Manual (2015), p. 70 [ 6 ]). External validity considers the generalizability of findings to a broader (more representative) population [ 6 ]. See appendix VII in the USPSTF report for criteria on research design hierarchy and the rating system used for scoring internal and external validity [ 6 ]. See Fig. 1 for summary of evidence rating, and the Supplemental Table for rating of each article.

Original literature review

Through review of the literature, we identified 56 articles which fit our criteria of having original data, answering a key question about DS and types of CHD, in humans, and reported on more than 5 cases (Fig. 1 , Table  1 ). These studies were published from 1950 to 2019, and used various study designs including: cohort studies [ N  = 22], cross-sectional studies [24], case-control studies [10], and case-series [2]. The study methods included: retrospective review [24] registries and databases [26], prospective screening programs [5], and parent survey [3]. Nearly all studies reported on a cohort, of which some were population-based samples [23] and some reported data longitudinally [5]. Some studies compared those with DS and CHD to those with DS without CHD. In addition to the bracketed number of studies, please see the Supplemental Table for specific details on each of the 56 studies.

Data extracted from original literature review which addressed one of our four key questions are presented below. We report studies based in the United States followed by international results.

Eighteen articles answered this key question from a variety of locations

In the United States, in national discharge data of 11,372 DS births, approximately 36% recorded selected cardiac malformations in 2007 [ 9 ]. Publications from the population-based National DS Project reported prevalence of CHD in infants with DS; in 2008, 649 of 1469 (44.2%), and in 2011, 483 of 1079 (44.8%) [ 10 , 11 ]. Prior, data from the population-based registry, the California Birth Defects Monitoring Program, reported CHD in 385 of 687 (56%) infants with DS in one publication [ 12 ], and in another 1620 of 2894 (56%) infants with DS had a cardiovascular system birth defect [ 13 ].

Publications from the population-based Metropolitan Atlanta Congenital Defects Program (MACDP) found 227 DS cases, of which 44% had CHD in 1989 to 1995 [ 14 ], and in 1968 to 1989 saw that 173 of 552 DS cases (33%) had cardiovascular malformations [ 15 ]. Over time, the frequency of these defects increased dramatically from about 20% in the early 1970s to more than 50% in the late 1980s ( p  = 0.0001), which the authors attributed to improvement in the ascertainment of cardiovascular malformations among infants with DS in a surveillance population [ 15 ].

To describe prevalence in CHD over time, eight additional international studies provided longitudinal data. In Sweden, among 2588 singleton live-born infants with DS between 1992 and 2012, 1387 infants had a diagnosed congenital heart defect, giving an overall birth prevalence of 54% which was similar over time [ 8 ]. In a multi-site European study of 14,109 cases with DS, of whom 6738 were live births, 306 fetal deaths, and 7065 terminations of pregnancy for fetal anomaly in 2000–2010, the overall prevalence of cardiac anomaly was 43.6% (95% confidence interval (CI): 42.4–44.7%) and had remained nearly constant [ 16 ]. A study of birth defects registries in France, Italy and Sweden in 1978–1993, found that cardiac defects were registered in 26% of the 5581 infants with DS [ 17 ]. In a Norwegian study no apparent increasing or decreasing trend in the prevalence of CHD in live born infants with DS was observed during 1994–2009 [ 18 ]. No significant change in prevalence was seen in Thailand with 64 of 149 with DS born in 2009–2013 who had CHD (43%) compared with 112 in 295 (38.6%) DS patients born in 1992–2002 [ 19 ]. In the United Kingdom, 342 of 821 live born infants (42%) in 1985–2006 had CHD [ 20 ]. Present a figure showing an increasing prevalence from approx. 30% in the late 1980s to approx. 50% in the early 1990s following which the prevalence seemed to stabilize around 40–50% until 2006 [ 20 ]. In Egypt, a downward trend in the prevalence of CHD (from 56.2% in the birth cohort 1992–1996 to 25% in the birth cohort 2012–2016) was observed in one clinic ( p  < .001) [ 21 ], while in another, the proportion of infants with DS and CHD increased from 29.8% in 1995 to 48.2% in 2000 [ 22 ].

Prevalence of CHD was reported at single time points in two international studies, including: 207 of 482 (43%) children with DS in the Netherlands born 2003–2006 [ 23 ] and 224 of 394 (56.9%) infants with DS in Korea in 2005–2006 [ 24 ]. One article was initially included, but on critical review was identified to have exclusion criteria which would make results regarding prevalence not generalizable, and is excluded from Fig.  2 [ 25 ].

CHD total prevalence. Overview of studies (assessed as population-based) reporting total prevalence of CHD among all DS patients. Studies are ordered according to period of birth midpoint/study period midpoint. CHD: congenital heart defect. DS: Down syndrome

In summary, in the eighteen studies cited above, we found that the total prevalence of CHD in DS ranged from 20 to 57.9%, mean 44.8% in DS patients born from the early 1970s to 2015 (Fig. 2 ). Over time, studies show an increasing prevalence in the late 1980s-early1990s from around 30% to around 50% following which the prevalence seems to stabilize around 40–55% until 2015 (Fig. 2 ). The findings indicate an apparent increase in reported CHD prevalence in the first 10–15 years of this period from around 20–30% to around 40–55%. The total prevalence rates varied over time: increased in Atlanta from 1970s to 1980s due to increased CHD ascertainment [ 15 ], decreased in Egypt from 1992 to 1996 to 2012–2016 [ 21 ], and was unchanged in Sweden from 1992 to 2012, in Europe from 2000 to 2010, and in Thailand from 1992 to 2013 [ 8 , 16 , 19 ].

Fifteen studies in the United States specified the types of CHD

With the study population in a single city [2] of Atlanta [ 14 , 15 ], specific states [7] including Alabama [ 26 ], California [ 12 , 13 ], Massachusetts [ 27 ], Minnesota [ 28 ], Pennsylvania [ 29 ] and Texas [ 30 ], regions [2] of Maryland / Washington DC / Virginia [ 31 ], and Maryland / Pennsylvania [ 32 ], or multiple states [4] [ 5 , 10 , 11 , 25 ]. These studies used databases, registries, and clinical records, and were all retrospective reviews. None of these fifteen studies described the type of CHD longitudinally.

Thirty-nine articles outside the United States provided data on the type of CHD in DS

Five studies in North America including: Canada [ 33 ], Mexico [ 34 ], Jamaica [ 35 , 36 ], and Guatemala [ 37 ]. Two studies in South America, including: Brazil [ 38 , 39 ]. Eleven in Europe including: Italy [ 40 ], Norway [ 18 ], Germany [ 41 ], United Kingdom [ 20 ], Netherlands [ 23 ], Europe (multiple countries) [ 42 ], Ireland [ 43 ], Portugal [ 44 ], France [ 45 ], England [ 46 , 47 ]. Eleven studies in Asia including: Malaysia [ 48 ], Thailand [ 19 ], Saudi Arabia [ 49 ], Pakistan [ 50 ], Korea [ 24 ], Singapore [ 51 ], India [ 52 ], Oman [ 53 ], Turkey [ 54 ], Turkey [ 55 ], Japan [ 56 ]. Seven studies in Africa including: Ethiopia [ 57 ], Algeria [ 58 ], Egypt [ 21 ], Morocco [ 59 ], Libya [ 60 ], Sudan [ 61 ], Egypt [ 22 ]. One study from Australia [ 62 ]. The type of CHD for all studies is reported in the Supplemental Table and summarized in Fig.  3 (including studies where CHD types are reported as proportion of DS patients) and Fig.  4 (including studies where CHD types are reported as proportion of all CHD types found). The figures show variable proportions of types of defects across periods of birth/study periods. In Fig. 3 , the majority of studies covering the period approx. Late 1960s to mid 1990s observe a greater proportion of complex defects (atrioventricular septal defect (AVSD), aortic arch abnormalities, tetralogy of Fallot, transposition of the great arteries, and single ventricle hearts) compared with shunt defects (isolated ventricular septal defect (VSD), isolated atrial septal defect (ASD), and isolated patent ductus arteriosus). In contrast, studies covering later years more often find the proportion of shunt defects exceeding the proportion of complex defects. In studies reporting on the number of CHD types out of all CHDs covering the period 1968–2018 (Fig. 4 ) shunt defects were consistently reported at higher proportions than complex defects.

Distribution of CHD types among DS patients. Proportion of DS patients with a given CHD grouped according to [ 15 , 8 ]: complex defects (AVSD, aortic arch abnormalities, tetralogy of Fallot, transposition of the great arteries, and single ventricle hearts), valve defects (aortic, pulmonary, and mitral-tricuspid valve defects), shunt defects (isolated VSD, isolated ASD, and isolated patent ductus arteriosus), and other defects [ 15 ]. do not report prevalence rates for the latter three groups according to year of birth, so for this study only proportions of complex defects are displayed in the figure. CHD: congenital heart defect. DS: Down syndrome. AVSD: atrioventricular septal defect. VSD: ventricular septal defect. ASD: atrial septal defect

CHD types as proportion of all CHDs. Frequencies of CHD types out of the total number of CHDs grouped according to [ 15 , 8 ]: complex defects (AVSD, aortic arch abnormalities, tetralogy of Fallot, transposition of the great arteries, and single ventricle hearts), valve defects (aortic, pulmonary, and mitral-tricuspid valve defects), shunt defects (isolated VSD, isolated ASD, and isolated patent ductus arteriosus), and other defects. CHD: congenital heart defect. DS: Down syndrome. AVSD: atrioventricular septal defect. VSD: ventricular septal defect. ASD: atrial septal defect

Six articles described the type of CHD longitudinally

In the United States, one study found an increasing prevalence during the 1980s of ascertained patent ductus arteriosus, endocardial cushion defects and ASD [ 15 ]. In Sweden, the risk of complex CHD (as defined in Figs.  3 and 4 ) decreased over time: compared with 1992 to 1994, the risk in 2010 to 2012 was reduced by almost 40% (adjusted risk ratio 0.62, 95% confidence interval 0.48–0.79) [ 8 ]. In contrast, chances for isolated VSD or ASD showed significant increases during later years, and although AVSD was far more common than VSD in 1992 to 1994, they were equally common in 2010 to 2012 [ 8 ]. Results from the United Kingdom, may support this finding [ 20 ]. Here, the proportions of ASD increased from approx. 9% in 1985–1989 to approx. 19% in 2000–2006 (our estimates based on the Fig. 3 in the article by Irving et al. [ 20 ]).

However, a 28-country, population-based study using congenital anomaly registries in Europe in 2000–2010 found no evidence of a trend in the proportions of births with DS with a severe cardiac anomaly (either of: single ventricle, hypoplastic left heart, hypoplastic right heart, Ebstein anomaly, tricuspid atresia, pulmonary valve atresia, common arterial truncus, AVSD, aortic valve atresia/stenosis, transposition of great vessels, tetralogy of Fallot, total anomalous pulmonary venous return, and coarctation of aorta) since 2000 [ 16 ]. There was no observed change in prevalence of ASD and VSD among births with DS over the 10 years of study [ 16 ]. The authors suggested that population screening for DS and subsequent terminations has not influenced the prevalence of specific congenital anomalies in these European infants [ 16 ]. Similarly, there was no apparent trend towards lower prevalence of AVSD among live born DS patients in Norway in 1994–2009 [ 18 ]. An Egyptian study found a decreasing prevalence of isolated CHD (as opposed to multiple CHD) from 56.2% in the birth cohort 1992–1996 to 19.8% in the birth cohort 2012–2016 [ 21 ].

In summary, in the included articles, the type of CHD reported varies greatly (Fig. 3 ). The studies which provided longitudinal data differed in the location and year; there was no clear consensus if, or how, the prevalence of specific types (complex, or severe) of CHD were changing over time.

Seven articles addressed this key question regarding CHD severity

In the United States during 2000–2014, neonates with DS who died were significantly more likely to have the diagnosis of complete transposition of the great vessels (37.5 vs 7.5%, respectively), double outlet right ventricle (17.7 vs 7.4%, respectively), Ebstein’s anomaly (29.4 vs 7.4%, respectively), left-sided obstructive lesion (14.9 vs 6.9%), or pulmonary venous abnormality (26.1 vs 7.5%, respectively) compared to those who survived [ 5 ]. Rates of surgical management were reported in two studies: in one study, all with AVSD underwent surgery [ 49 ], and in a second study, surgery was the most common treatment modality (54.3%) [ 59 ].

In Norway, the five-year hazard ratio for death was highest for children with conotruncal defects, then AVSD and then other CHDs [ 18 ]. Mortality was especially high for children with DS who had extracardiac malformations with 93% dying in first year [ 18 ]. In Malaysia, one study reported on children with DS and CHD of which 30% of lesions closed spontaneously, 35% underwent surgery / intervention, 9% died before surgery / intervention, and 10% were treated with comfort care [ 48 ]. The authors assess proportions of cases in each DS patient category for each birth year in 2006–2015, however, the small numbers limit interpretation of potential changes in time. The overall 1-, 5-, and 10-year survival rates for cases with DS and CHD were 85.5, 74.6, and 72.9%, respectively, with 31% of deaths being cardiac related [ 48 ]. One-year survival was reported comparable in 2006 (87%) and 2015 (84%) [ 48 ]. A German study found a temporal change in treatment: the likelihood of surgical treatment increased from 0% for DS patients born in the 1950s/1960s to 2.1% in the 1970s and 85.6% among patients born after 2000 [ 41 ]. Further, the authors report the proportion of patients developing Eisenmenger syndrome decreasing from 53.3% in the earliest birth cohort to 0.5% in the latest birth cohort. Results from the United Kingdom supports the improved prognosis: compared with 1985–1995, DS infants in 1996–2006 more often underwent surgery (62% vs. 72%), had lower mortality following surgery (30% vs. 5%) including lower early postoperative mortality [ 20 ]. Overall, the 1-year survival among DS infants with CHD improved from 82 to 94% from the early to the late cohort [ 20 ].

Some studies specified that all had an echocardiogram [ 49 , 59 ], while others relied on retrospective review and were limited by documentation and the possibility that echocardiogram may not have been performed for all. Echocardiogram appeared to be generally accepted as the diagnostic standard. One study evaluated if screening with physical examination, ECG, and chest X-ray is an effective method of identifying which infants with DS should have an echocardiogram, and found that this method would have resulted in 69 (17%) fewer echocardiograms without missing infants with major CHD, but missing cases of patent ductus arteriosus and ASD [ 25 ]. In a similar study investigating the ability of clinical examination, chest X-ray, and ECG soon after birth separately and in combination to detect CHD, the three modalities combined showed a sensitivity of 71% and a specificity of 91% [ 43 ]. Another study assessed the accuracy of physical examination alone for identifying CHD in neonates with DS and report a sensitivity of 80% and specificity of 56%, concluding that physical examination is not a sufficient screen for CHD [ 29 ].

Through literature review using MeSH terms in PubMed, we identified 56 articles which provided original data about DS to answer one of our key questions on prevalence, types of CHD, severity, and screening. We found that:

The total prevalence of CHD in DS ranged from 20 to 57.9% in 18 studies; the earliest studies indicated an increase in prevalence, while in later decades, the reported prevalence appeared constant around 40–50% (Fig. 2 ) The total prevalence rates over time were reported in 9 studies and were: increased in Atlanta from 1970s to 1980s due to increased CHD ascertainment [ 15 ], increased in the United Kingdom from the late 1980s to early 1990s [ 20 ], decreased and increased at two sites in Egypt from 1992 to 1996 to 2012–2016 and 1995 to 2000, respectively [ 21 , 22 ], and unchanged in Sweden from 1992 to 2012, in Europe from 2000 to 2010, and in Thailand from 1992 to 2002 to 2009–2013 [ 8 , 16 , 19 ].

The types of CHD identified varied considerably between studies (Figs. 3 and 4 ). The six studies which provided longitudinal data differed in location and year; there was no clear consensus if the prevalence of specific types of CHD in DS changed over time, although some studies indicated a trend towards increasing relative proportion of milder lesions.

Seven articles addressed the key question of CHD severity. These showed links to mortality for specific types of CHD in DS, and some reported on rates of surgical (and non-surgical) treatment. Generally, the last decades have shown improvements in treatment outcomes and mortality.

Echocardiogram remains the accepted diagnostic approach, though some have evaluated additional approaches and timing and frequency of echocardiogram.

In conducting this literature review, a number of confounding factors of the studies arose. First, the source of information differed between studies with some reviewing medical records and others employing registry data. Varying data quality may have been an issue – for example the extent to which a CHD diagnosis was captured in databases/registries. We initially coded CHD as published by authors, without additional interpretation or modification. For subsequent figures CHD types were grouped according to [ 15 ]. and we considered endocardial cushion defect and complete atrioventricular canal as AVSD [ 8 ](Figs. 3 and 4 ). Differences in classification of CHD among the studies could lead to validity issues as we try to summarize the available literature. As such, Figs. 3 and 4 should be interpreted with caution. Additionally, the method in which CHD was counted in studies differed, with some studies presenting results in number of defects (with multiple defects possible for a single patient) while some report results in number of patients. Also, in many studies the specific CHD was listed, but some studies grouped CHD in a variety of ways, including: right- or left-sided CHD, severity of CHD, primary or secondary CHD, isolated or complex CHD, or size of the VSD. In defining CHD some studies include isolated PDA, while others only include if remains open at given age [ 29 ]. There may be a selection bias in studies: for example, if severe cases of CHD in DS are more likely to have a clinic visit, the prevalence of severe CHD in a single-center study from this clinic could be falsely high.

Over the years, several factors may have impacted on prevalence, diagnosis, and management of CHD in DS. These factors are important to take into account when answering our key questions based on the results from 56 studies. In one study, the prevalence of CHD increased from 1970s to 1980s due to improvement in the ascertainment of cardiovascular malformations among infants with DS [ 15 ]. Both improved echocardiography techniques and availability of cardiac testing could impact the reported prevalence rates over time. Additionally, improved cardiac care, and surgical outcomes for CHD as a whole over time could impact neonatal mortality and prevalence of CHD in children with DS. The impact of elective terminations could impact how many infants are born with DS [ 2 ]; and it is possible that those with DS and prenatal diagnosis of CHD could undergo elective terminations at a rate different from those with DS and no CHD. Over the last decade, prenatal diagnosis of DS has become more widely available through use of cell-free fetal DNA (cff-DNA). A prenatal diagnosis of DS through cff-DNA could lead to additional fetal testing and identification of CHD prenatally. Increased elective terminations due to the advent of cff-DNA and fetal cardiac testing, could impact both the overall prevalence of CHD in DS, as well as the type of CHD. Most of the 56 studies we identified focused on CHD postnatally, but a multi-site European study of 14,109 cases with DS reported the proportion with any cardiac anomaly in live births and fetal deaths (43.6% of 3068 (95% CI: 42.4–44.7%)), and in all terminations of pregnancy for fetal anomaly (8.1% of 570 (95% CI: 7.4–8.7%)), and in terminations of pregnancy for fetal anomaly who had a postmortem examination (18.1% of 220 (95% CI: 16.0–20.4%)), but had under-reporting of medium and low mortality cardiac anomalies in TOPFAs [ 16 ].

Location of study may impact findings, and how we summarize results. For example, local resources may differ by location and impact some of the confounding factors described above, such as: the timing of diagnosis of DS or CHD, the availability of echocardiography and cardiac testing, the availability and uptake of prenatal diagnosis of DS (including cff-DNA testing in later years), the quality and availability of pediatric cardiac care, and the availability and outcomes of surgical management. In addition, there may be differences in racial and ethnic composition of the population by location. In one study of infants with DS, CHD was the most frequently reported cause of death from death certificates and the case fatality rate among infants with DS was significantly higher among blacks than whites, with the greatest racial disparity observed among infants without CHD who died in the post-neonatal period [ 63 ]. The genetic makeup of the population may lead to differences in the prevalence of CHD in DS, for example, in instances of consanguinity, as found in one study in which parental consanguinity was an independent predictors of CHD in children with DS, with adjusted odds ratio (OR) of 1.9 [ 21 ]. Altogether, local trends in CHDs in DS are potentially overshadowed in studies including data from different populations and may impact on our ability to assess general trends.

There may be other covariates which differ among these 56 studies, and influence the answers to our key questions. Lack of maternal folic acid supplementation was more frequent among infants with DS and atrioventricular septal defects (OR 1.69; 95% CI: 1.08–2.63; p 5 0.011) or atrial septal defects (OR 1.69; 95% CI, 1.11–2.58; p 5 0.007) than among infants with Down syndrome and no heart defect [ 10 ]. Parental origin of chromosome 21 may be relevant; one study found that CHD were more frequent in cases with a maternally derived extra chromosome 21 [ 64 ].

This literature review is limited by the information presented and published in the existing medical literature. For some of the confounding factors such as naming, diagnosing, counting, grouping and selecting cases, it would be useful to have a standard nomenclature or protocol when describing CHD in DS to allow studies to be compared. Also, when including results in Figs.  2 , 3 and 4 , we sorted studies based on midpoint of birth period/study period though some span a great number of years with overlapping time periods, which limits the interpretation of our figures. In addition, the 56 articles were identified through searching with MeSH terms and the PubMed database; relevant articles may have been missed and we have been made aware of three such articles [ 65 , 66 , 67 ]. Additionally, changes over time and by location, complicate our ability to combine results of studies and draw broad conclusions. To address this, we present original data from studies and our full review data in the Supplemental Table .

Future studies to update current findings of CHD in DS could address some of the gaps in the literature which we have highlighted, including: considering use of a standard nomenclature and protocols to increase consistency across sites. Ideally, an international population-based database could be created to focus on CHD in DS, and could begin to collect prospective information from time of initial diagnosis, including prenatal diagnoses, then tracking diagnostic outcomes and treatments longitudinally. Regional changes could also be due to local issues, and more longitudinal studies assessing changes in time and taking local factors into consideration may also provide important insights.

CHD has remained a consistently common co-occurring condition in DS for decades. Recent studies show there may be trends in specific types of CHD with increases in isolated, less severe types and decreased types which are complex, more severe, however not all studies support this. Future studies would ideally be international, population-based, longitudinal, use consistent nomenclature, and account for factors which impact prevalence and severity of CHD.

Availability of data and materials

The data that support the findings of this study were derived from the following resources available in the public domain: PubMED at https://www.ncbi.nlm.nih.gov/pubmed/ and the full data from our review is listed in the Supplemental Table.

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SLS conceptualized the project, conducted the literature reviews, critically-reviewed articles, and analyzed, interpreted the data, and drafted first version of the manuscript. EHS reviewed literature review data, interpreted articles, created figures and tables, revised manuscript. All authors read and approved the final manuscript.

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Dr. Santoro receives research funding from the National Institutes of Health. Dr. Santoro receives research funding from the LuMind IDSC Down Syndrome Foundation to conduct clinical trials for people with DS and serves on the Professional Advisory Board for the Massachusetts Down Syndrome Congress. The other authors have no conflicts of interest relevant to this article to disclose.

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Santoro, S.L., Steffensen, E.H. Congenital heart disease in Down syndrome – A review of temporal changes. J Congenit Heart Dis 5 , 1 (2021). https://doi.org/10.1186/s40949-020-00055-7

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MINI REVIEW article

Development of down syndrome research over the last decades–what healthcare and education professionals need to know.

• 1 Division of Obstetrics and Feto-Maternal Medicine, Department of Obstetrics and Gynecology, Medical University of Vienna, Vienna, Austria
• 2 Research Unit Developmental Psychology, Department of Developmental and Educational Psychology, Faculty of Psychology, University of Vienna, Vienna, Austria

Down syndrome (DS) is the most prevalent neurodevelopmental disorder, with a known genetic cause. Besides facial dysmorphologies and congenital and/or acquired medical conditions, the syndrome is characterized by intellectual disability, accelerated aging, and an increased likelihood of an early onset Alzheimer's disease in adulthood. These common patterns of DS are derived from the long-held standard in the field of DS research, that describes individuals with DS as a homogeneous group and compares phenotypic outcomes with either neurotypical controls or other neurodevelopmental disorders. This traditional view has changed, as modern research pinpoints a broad variability in both the occurrence and severity of symptoms across DS, arguing for DS heterogeneity and against a single “DS profile.” Nevertheless, prenatal counseling does not often prioritize the awareness of potential within-group variations of DS, portraying only a vague picture of the developmental outcomes of children with DS to expectant parents. This mini-review provides a concise update on existent information about the heterogeneity of DS from a full-spectrum developmental perspective, within an interdisciplinary context. Knowledge on DS heterogeneity will not only enable professionals to enhance the quality of prenatal counseling, but also help parents to set targeted early interventions, to further optimize daily functions and the quality of life of their children.

Introduction

Down syndrome (DS) is the most common neurodevelopmental disorder with known genetic causes, and an incidence of 1 in 691 live births ( 1 ). This suggests that ~417,000 people with DS live in Europe ( 2 ). Currently, an expansive menu of prenatal diagnostic methods for DS is spreading worldwide, advancing the diagnosis of DS from postnatal to prenatal ( 3 ). Giving an expectant parent a fetal diagnosis of DS provides them with 2 options: keeping or terminating their pregnancy, following the lack of a cure ( 4 ).

Prenatal counseling is crucial for providing parents with an accurate picture of DS so that informed decisions can be made in the context of their own beliefs and values ( 3 ). Although studies are still examining the nature of DS, portraying the expected neurodevelopmental outcomes of affected children remains challenging. Indeed, retrospective studies indicate that parents felt that the information received during prenatal counseling was inaccurate, outdated, and unbalanced, and either too negative or too optimistic ( 5 – 7 ). Without appropriate professional training or updated professional development regarding the individual variability in outcomes associated with DS, prenatal counselors might present expectant parents with inaccurate information or impressions. Therefore, expectant parents may not receive the level of information needed. Accordingly, all professionals working with families affected by DS must be aware of the most current scientific research regarding the heterogeneity of phenotypic outcomes ( 8 ).

This mini-review closes an existent literature gap by providing a concise update on the available information on within-group variations in the DS phenotype of infants, children, and adolescents for professionals. First, a gross outline of DS research is given, focusing on the significant paradigm shift from a group- to an individual-level approach. Second, the current knowledge on significant within-group variations of DS in cognitive, behavioral, emotional, and olfactory functioning is summarized. Finally, the review concludes by arguing that only an interdisciplinary approach allows for the description of realistic individual DS profiles. The scope of this review is to further increase the awareness on DS heterogeneity concerning developmental outcomes.

A Paradigm Shift in DS Research: From a Group- to Individual-Level Approach

DS research dates back to 1866, when the English physician John Langdon Down systematically described the syndrome for the first time ( 9 , 10 ). In addition to intellectual disability (ID), he chronicled a distinct physical phenotype of individuals with DS, conjecturing that they were “born to the same family” (page 9) ( 10 , 11 ). The century following his pioneering work was filled with publications of diverse medical case studies documenting a range of physical traits and medical comorbidities, leading to various etiologies ( 10 , 11 ).

Almost 100 years later, the French pediatrician and cytogeneticist, Jérôme Lejeune, identified the genetic basis of DS in 1959 as an extra copy of all or part of chromosome 21 ( 10 , 12 ). The discovery of “trisomy 21” paved the way for further research, to elucidate genotype-phenotype-relationships ( 13 , 14 ). Since its original description, classical DS research has analyzed the syndrome's phenotypes relative to neurotypicals and/or other neurodevelopmental disorders, hence providing group-level data that have advanced our basic knowledge of DS ( 8 ). It is characterized by both typical physical features that make the syndrome “instantly recognizable” (page 8) and ID ( 11 ). Common appearance includes craniofacial dysmorphologies, short stature, low muscle tone, and a proportionally large tongue. Additionally, medical comorbidities, such as sleep apnea, visual and/or hearing problems, congenital heart defects, and altered behavioral, hematopoietic, endocrine, gastrointestinal, neurological, and musculoskeletal conditions, are linked to DS ( 10 ).

Most of these medical problems are treatable with pharmacotherapy and/or surgical interventions. Therefore, among the key focuses in recent DS research is the widespread field of neurocognition, associating DS with weaknesses in motor ability, auditory processing, verbal short-term memory, and expressive language. However, relative strengths in visuospatial processing, receptive language, and some aspects of social functioning have been reported ( 15 – 18 ). Further, DS is associated with accelerated aging and an increased likelihood of the early onset of Alzheimer's disease (AD) ( 18 ).

Although the generalizability of the characteristics of DS has been questioned repeatedly in the history of DS research, the group-level approach is a long-held standard ( 19 , 20 ). However, this traditional view has changed, following a growing number of studies, which pinpoint significant within-group variations across individuals with DS at many levels of description. Pioneer studies have launched this paradigm shift, from a group to an individual-level approach, by highlighting significant individual differences in genetics, cell biology, brain research, and subsequently, parts of cognitive research on DS [see ( 8 )]. These studies suggest that this heterogeneity may be continued in DS phenotypes ( 8 ). The following review aims to supplement the prevailing knowledge about the variability of the developmental outcomes of DS by addressing this issue from an interdisciplinary and applied science perspective, as this practical information may be the most useful for professionals to pass to expectant parents.

Infants, Children, and Adolescents With DS: Variability in Developmental Outcomes

Acquisition of developmental milestones.

Generally, it was assumed that infants and children with DS reached developmental milestones in the same linear fashion as their non-DS peers, but at later chronological ages. This view is too simplistic, as the age of acquiring milestones among infants and children with DS is reported to vary significantly ( 21 , 22 ). For example, the mean age at the onset of babbling is ~15 months, with an interindividual variability of 10 months. Similarly, sphincter control is acquired by DS children at an approximate age of 44 months, with 22 months of interindividual variability ( 22 ). Notably, Locatelli et al. suggested that the age at which developmental milestones are reached influences the subsequent development of diverse cognitive domains significantly ( 21 , 22 ).

Intellectual Disability (ID)

ID, defined by an intelligence quotient (IQ) score of <70, is reported to be universal in the DS population. However, this construct presents in DS with large interindividual variability ( 23 ). The majority of individuals with DS fall within the severe (IQ 20–35) to mild (IQ 50–69) range of ID. However, some cases reach IQ scores equivalent to children without ID ( 14 , 24 ). Research on the developmental trajectories of cognitive function in neurotypicals shows that IQ is a construct that remains relatively stable and consistent across ages. A slight decline was observed only in older adults ( 14 ). Conversely, DS research has identified a linear decline in IQ scores as development progresses, starting in the first year of life (i.e., cognitive gains do not keep pace with chronological age). Notably, single IQ levels and the degree of cognitive decline vary across the DS group ( 14 ).

Language is another cognitive domain that generates significant differences among individuals with DS. DS is associated with weaknesses in expressive language and a relative strength in the receptive language ( 18 ). The available literature reports developmental delays in both language domains, becoming apparent no later than age five, yet with wide individual differences ( 25 , 26 ). Regarding vocabulary acquisition and growth, longitudinal studies reported an existing continuum, ranging from non-verbal children to those with a vocabulary close to the normal range ( 27 , 28 ). Children with DS use gestures as a means of communication, which has been positively associated with the development of spoken vocabulary ( 29 ). Nevertheless, significant individual variability in the extent to which this “gestural advantage” is used has been demonstrated by empirical data ( 30 ). All within-group differences in language development persist into adulthood ( 26 ).

Memory and learning deficits are universal characteristics of DS and are known to become more pronounced as development progresses ( 14 ). In classical DS research, the findings of affected memory domains are mixed, suggesting underlying variability ( 18 ). Indeed, scientific data demonstrate that there are individual differences in both implicit and explicit memory ( 8 , 31 ). Regarding the latter, significant within-group variations are described for short-term verbal and long-term visual memory ( 8 ). Individuals with DS often show deficits in processing local detail. Therefore, classical DS literature claims that individuals with DS were “global processors.” However, this preference for global over local processing does not always occur in the DS population. Therefore, individuals with DS cannot be simply categorized into one of these processing styles ( 32 ).

Executive Function (EF)

EF encompasses a range of cognitive processes involved in goal-oriented behavior, and is a domain in which individuals with DS are shown to have pronounced difficulties ( 33 ). The areas of working memory, attention, planning, and inhibition are considered particularly challenging for individuals with DS; emotional control is considered a relative strength ( 34 , 35 ). However, significant individual differences in EF across the DS group have become evident ( 33 , 36 ). Within-group variations in auditory attention have been identified via electrophysiological measurement among toddlers with DS, data that also predict differences in language abilities as development progresses ( 37 ). Patterns of executive dysfunction appear to be relatively consistent across development until adulthood ( 23 , 34 ).

Adaptive Behavior (AB)

Children and adolescents with DS are known to be severely impaired in AB, which subsumes behavioral skills that enable them to function independently in their everyday life ( 23 , 38 ). Generally, AB encompasses 4 domains: socialization, communication, daily living, and motor skills ( 23 ). Significant within-group variations were apparent for all the 4 domains. For example, DS has been associated with sociability, friendliness, affection, empathy, good competence in forming relationships, and high tendency to smile ( 39 ). Yet, children and adolescents with DS are also considered stubborn, to show little accommodation to social partners, and approach strangers inappropriately ( 40 ). Some individuals with DS have even deficits in socialization to the extent of a comorbid diagnosis of autism ( 41 ).

Maladaptive Behavior (MB) and Psychiatric Comorbidities

MB encompasses a range of behaviors that impede an individual's activities of daily living or the ability to adjust to and participate in particular settings ( 23 ). Approximately 1/4 to 1/3 of individuals with DS exhibit clinically significant levels of maladaptive behavioral concerns ( 42 – 44 ). This behavioral construct is another domain that yields significant within-group differences ( 21 , 23 , 45 ). More difficulties with “anxious-depressed” symptoms are observed among adolescents than younger children with DS ( 23 ). Children with DS often exhibit externalizing behavior ( 46 ). The manifestation of MB is significantly higher when neurobehavioral disorders are concomitant ( 47 – 49 ). According to the available literature, the manifestation of psychiatric features, including autism, depression, and the attention-deficit/hyperactivity disorder, vary significantly, between 6 and >50% ( 42 , 44 , 50 , 51 ). Channell et al. underscored within-group differences in the behavioral domain by subtyping a >300-person DS group, hence identifying a separate “behavioral” class as described in Table 1 ( 23 ).

Table 1 . Characterization of the 3-class model of individuals with DS ( N = 314; 6–25 years) based on the variability observed in cognitive and behavioral measures, identified by Channell et al. ( 23 ) using a latent profile analysis.

Emotional Functioning

The emotional profiles of individuals with DS have remained underexplored, which could be attributed to the assumed stereotype of high sociability in this population ( 52 , 53 ). Available literature provides variable data about whether children and adolescents have difficulties in emotional functioning ( 52 ). Whereas, some studies negate differences in identifying basic emotion in faces between DS and non-DS groups, other scientific reports indicate that children and adolescents with DS have impairments in this emotional skill [see Roch et al. ( 52 )] ( 54 – 57 ). Deficits in recognizing facial expressions were not generalized to all emotions, but mostly to fear ( 52 , 58 ). Other studies report impairments in determining feelings, including surprise, anger, and neutral expression ( 40 , 58 – 61 ). Some studies pinpoint problems in ascertaining negative emotions ( 40 ). Moreover, an inability to distinguish between fear and sadness is another atypical pattern that has been reported among some individuals ( 58 ). Most of these deficits are identified during infancy and childhood. Therefore, a negative impact on the subsequent development of interpersonal relationships is discussed ( 52 ). As previously mentioned, studies have exclusively gathered data at the group level. Moreover, further research should examine whether inconsistencies in findings across studies can be attributed to underlying within-group variations.

Olfactory Functioning

The number of studies on olfactory function among patients with DS is limited and relatively out of date ( 62 – 69 ). Historical studies have described olfactory deficits in the DS population for many years ( 62 , 63 , 65 , 70 ). Because rhinologic pathologies have been ruled out by studies showing nasal function in DS as comparable to controls, central-nervous causes are suggested ( 64 ). More recently, Cecchini et al. described olfactory function as severely impaired among adults with DS ( 71 ). They found a positive correlation between odor identification and cognition ( 71 ). To date, the largest study, which included people with DS and under 18 years, described a minimal impairment of olfactory functioning among children and adolescents (9–17 years), which became pronounced in young adulthood (18–29 years) and was the lowest in adulthood (30–50 years) ( 72 ). Of the three groups, DS, IQ, and age-matched controls, significant within-group differences were evident only in the DS group ( 72 ). However, large and detailed analyses of olfactory function in light of within-group variations among children and adolescents with DS are still lacking. Odor identification deficits are considered a valid non-invasive early marker of AD. Therefore, future research on whether olfactory dysfunction can help to ascertain the subset of children and adolescents with DS that will later develop AD is warranted.

Alzheimer's Disease (AD)

Although the issue of AD appears outside the scope of this review, the following considerations must be made when the heterogeneity of DS is discussed with expectant parents from a full-spectrum developmental perspective. Owing to a shared genetic predisposition, individuals with DS have an increased likelihood of developing early onset AD in adulthood ( 18 ). Prevalence rates of dementia among the DS population vary significantly in the literature, from 8 to 100% ( 18 , 73 ). Recent brain research has identified Alzheimer's plaques among some children with DS, that is, as early as 8 years of age, whereas some DS brains show no plaques until early adulthood ( 14 , 26 ). Although AD neuropathology occurs in virtually all individuals with DS over the age of 30, only a subset of people develop clinical symptoms of dementia ( 26 , 74 , 75 ). Hence, it is apparent that the widespread interindividual variability, typical for DS, is a pivotal feature not only during development, but also during aging ( 26 ). Aging is part of the continuous lifespan development. Accordingly, some authors argue that AD should be considered a disease that occurs during development, rather than aging ( 76 ).

Extrinsic Influencing Factors of Developmental Outcomes of Infants, Children, and Adolescents With DS

Medical comorbidities.

In addition to cognitive limitations, parents must be informed that there is a list of medical comorbidities associated with DS. Some of them, including congenital heart defects (CHD), seizures, visual and/or hearing impairments, autism, and sleep disruptions, are known to moderate cognitive functioning ( 18 ). Analogous to neurodevelopmental outcomes, both the occurrence and expression of congenital and/or acquired medical complications are variable ( 18 ). For example, 41–56% of infants with DS are born with a CHD, with an atrioventricular septal defect that occurs between 31 and 61% being the most common form ( 77 , 78 ). Cognition, gross motor skills, and language are significantly worse among infants with DS and CHD, relative to peers without CHD, in some, but not in all related studies ( 79 – 81 ). For example, Alsaied et al. showed that children with DS and CHD, who undergo cardiac surgery during their first year, have no significant differences in neurodevelopmental outcomes at preschool and school age. However, as infants and toddlers, they were prone to poorer outcomes in receptive, expressive, and composite language compared to children with DS without CHD, suggesting that deleterious effects may be dependent on clinical management ( 82 ).

Home Environment

Another variable that affects the observed variability of DS phenotypes, which is influenced by the expectant parents, is the home environment. According to Karmiloff-Smith et al., the genetic syndrome changes the family context in terms of parent-child-interactions ( 8 ). D'Souza et al. demonstrated that parental depression, a disease linked to difficulties in responding to the child in a sensitive and consistent manner, explained deficits in expressive language development among children between 8 and 48 months of age with DS ( 83 ). Similarly, there is evidence that vocabulary development among children with DS is influenced by how parents respond to their children's communication. Deckers et al. argued that mothers with a higher level of education had a better ability to fine-tune their communication with their children with DS ( 28 ). Further demographic factors, including socioeconomic status, neighborhood demographics, and the availability of therapeutic resources, modulate the developmental outcomes of DS effectively ( 84 , 85 ). These data demonstrate that only an interdisciplinary approach that considers psychological, physical, and social parameters will enable professionals to accurately inform expectant parents on how the DS phenotype will be expressed in each individual.

Although DS has been examined for a long time, that is 155 years, it is still one of the least understood genetic ID syndromes. The most significant reason for this is the high degree of phenotypic variability observed in the DS population, an issue that professionals are often unaware of when discussing the diagnosis with expectant parents. However, DS research has advanced from a group to an individual-level approach, attempting to acknowledge within-group differences at many levels of basic science ( 8 ). To expand on this wealth of data, this mini-review has shed light on the available information on individual variability in the developmental outcomes of infants, children, and adolescents with DS from an applied science perspective, which will enhance the quality of prenatal counseling. Diverse developmental domains, including cognition, behavior, and emotional and olfactory functioning, have been discussed.

The evaluation of developmental outcomes from a full-spectrum perspective, however, must not only address different developmental domains, but also the change of phenotypes over time ( 86 ). Outcome variables are not completely intact or impaired uniformly throughout development, but manifest as variations at an early state, that may be magnified with age, ending up as either a strength or a weakness. Therefore, parents should be made aware that early development can be considered a critical window of opportunity to set adequate phenotype-specific interventions before deficits become severely pronounced ( 87 ). Thus, the maximization of individual potential is possible. In addition to psychological factors, other influencing variables must be considered by parents when the variability of DS phenotypes is discussed. According to Karmiloff-Smith who states that having a neurodevelopmental disorder changes both the social environment and physical status, only an interdisciplinary research approach can successfully describe valid profiles of individuals with DS ( 8 ).

The most convincing argument for emphasizing individual variability among DS groups and discussing them with expectant parents are both an average life expectancy of 60 years combined with an early onset of Alzheimer's disease in the DS population ( 18 ). Focusing on individual differences in the development of DS may be the best approach for exploring the risk and protective factors of AD ( 88 , 89 ).

Modern DS research shows that developmental heterogeneity has become increasingly validated ( 23 ). Moving forward, these up-to-date data must be disseminated under the supervision of professionals so that prenatal counseling can be optimized in quality, hence allowing parents to gain realistic expectations about the future of their children. Thus, more targeted treatments and interventions can be set to improve the daily function and quality of life.

Author Contributions

KW and SH designed the paper. KW did the literature research and wrote the manuscript. SH provided intellectual input and critically revised the manuscript. Both authors contributed to the article and approved the submitted version.

Conflict of Interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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Keywords: Down syndrome, trisomy 21, developmental outcome, phenotypic heterogeneity, Alzheimer's disease, medical comorbidities, social environment, prenatal counseling

Citation: Windsperger K and Hoehl S (2021) Development of Down Syndrome Research Over the Last Decades–What Healthcare and Education Professionals Need to Know. Front. Psychiatry 12:749046. doi: 10.3389/fpsyt.2021.749046

Received: 28 July 2021; Accepted: 22 November 2021; Published: 14 December 2021.

Reviewed by:

Copyright © 2021 Windsperger and Hoehl. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY) . The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

*Correspondence: Stefanie Hoehl, stefanie.hoehl@univie.ac.at

Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.

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Demographic Assessment of Down Syndrome: A Systematic Review

The objective of this study is to assess the evidence about the demographic transformation of the Down Syndrome population, with a specific focus on prenatal testing, and to identify sources frequently used for demographic assessment of Down Syndrome in the world. We reviewed existing studies on demographic transformations in the population with Down Syndrome, specifically birthrate indicators, under the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Statement. The searches were made in Medline (via EBSCO Host), Academic Search Complete (via EBSCO Host), PsycINFO (via EBSCO Host), Web of Science (Core Collection), Public Health Database (via ProQuest), and The Cochrane Library. The terms were developed through Medical Subject Headings (MESH) and American Psycological Asociation Thesaurus of Psychological Index Terms (APA). Full texts were reviewed if information was given regarding location and birthrate for a range of three years or more, and if the first and last year considered was within 1960 and 2019. We found 22 references with a period of study between 1960 and 2019 following the global spread of prenatal testing for Down Syndrome. We found a consistent association between prenatal diagnosis and birthrate, enough to explain the significant fall in the prevalence of Down Syndrome, a somewhat rising incidence of Down Syndrome related to increased maternal age and extension of fertility services in healthcare systems, a generalized use of specific congenital birth defect registries as the primary source of data, and an unclear influence of socio-cultural and territorial variables. Our findings can inform research, policy, and practice to improve the reproductive health and quality of life of the population with Down Syndrome.

1. Introduction

Down syndrome (DS) is the most common genetic abnormality associated with a varying degree of intellectual disability, some health and developmental effects, and peculiar physical features that give those with it a recognizable appearance. The causes that can explain this genetic alteration are mostly unknown, although it is well recognized that a high incidence occurs with increasing maternal age.

Demographic assessment is widely used in policy-making processes related to social protection, health care, and other public policies worldwide, mainly when there are significant differences in practices across different countries [ 1 ]. In this work, we make a demographic evaluation of the population with DS based on a key demographic indicator of incidence: birthrate as the number of infants with DS per 10,000 live births.

There are some hints on how the population with DS may be undergoing a major demographic transformation based on declining birthrates. This situation presents differences by countries that seem related, intuitively, to the influence of cultural factors, physician practices, and women’s decision-making regarding prenatal screening and diagnosis for DS [ 2 ].

The origins of prenatal diagnostic techniques began in 1955 [ 3 ]. From that moment, multiple methods for the diagnosis of chromosomal abnormalities followed each other [ 4 ]. In 1970, amniocentesis was able to diagnose DS with a high degree of certainty, and from then, the technique was spread rapidly in healthcare systems [ 5 ].

In 1984, the World Health Organization recommended the use of prenatal diagnostic techniques in all families at risk [ 6 ]. The incorporation of prenatal testing has resulted in promoting these techniques as part of the obstetric surveillance and screening programs [ 7 ]. Since 2011, non-invasive prenatal testing techniques have been developed and offered as an alternative to invasive testing to eliminate the risk of fetal loss [ 8 ].

After five decades of prenatal diagnosis, there is an intense debate about whether the widening and improvements in genetic counseling have resulted in a relative impact on the birth prevalence of DS [ 9 , 10 , 11 ] and may trigger a significant transformation in the demography of this population.

In the framework of the health-related domains of the International Classification of Functioning, Disability and Health (ICF) [ 12 ] and Convention on the Rights of Persons with Disabilities (CRPD) [ 13 ], the Disability Rights Movement has become increasingly vocal that prenatal diagnosis applied to DS could be considered discrimination against the disability [ 14 , 15 ].

The objectives of this study are (1) to weigh the evidence about the demographic transformation of the DS population trough birthrate, (2) to analyze factors likely to explain this demographic transformation with a specific focus on prenatal testing, and (3) to identify sources frequently used for demographic assessment of DS in the world. A systematized review was made under the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Statement to collect data on demographic transformations in the population with DS, specifically birthrate indicators.

Ultimately, the overall goal of the article is to offer critical information to determine the extent to which the demographic transformations of the population with DS around the world are debatable in light of compliance with the International Convention on the Rights of Persons with Disabilities (CRPD), and what implications they have for related public policies.

2. Materials and Methods

The review followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Statement. The aim of the screening was to capture all the relevant studies concerning the demographic transformations in the population with DS, specifically over birthrate indicators.

2.1. Search Strategy

We searched six databases: Medline (via EBSCO Host), Academic Search Complete (via EBSCO Host), PsycINFO (via EBSCO Host), Web of Science (Core Collection), and Public Health Database (via ProQuest). Search strategies and key words were developed based on Medical Subject Heading (MeSH) and APA Thesaurus of Psychological Index Terms and published search strategies ( Table A1 in Appendix A ). Additional relevant studies were hand-searched, and previous review articles were used for identification of studies not retrieved through the electronic database.

The authors developed the search strategy (Agustín Huete and Mónica Otaola), and one applied the search (Mónica Otaola). Terms outside from thesaurus are used if it was used during the last decades. The search strategy was based on the MESH and APA Thesaurus. The search used the following key terms based on the main aim of the study: (1) Down Syndrome Population: “Down Syndrome” (MESH), “Down’s Syndrome” (APA), “Trisomy 21”; (2) Demography: “Demography” (MESH), “Epidemiology” (MESH) (APA), “Incidence,” “Birthrate”; and (3) Prenatal testing: “prenatal diagnosis” (MESH) (APA), “prenatal screening,” “prenatal test.”

The review was developed in literature published between 1980 and 2019, as the birthrate prior to the 1970s was assumed to be unaffected by prenatal diagnosis [ 16 ]. There were no restrictions on the regions under study. The search only considered articles published in peer-reviewed journals in English and Spanish languages. Boolean operators (and, or, proximity) were used to construct and refine the search.

2.2. Inclusion Criteria

Sources retrieved from the six databases were selected for a full-text review if their title or abstract included explicit terms related to Down Syndrome and Demography. The criteria to avoid the risk of bias and choosing the literature were accomplished in the subsequent three phases: (1) title review, (2) abstract review, and (3) full-text review. The records were screened by the authors. Full texts were reviewed if information was given regarding location (city, region, country) and birthrate for a range of three years or more, and if the first and last year considered was within 1960 and 2019.

We excluded: (1) duplicate publications; (2) articles with estimated data; (3) periods under study of less than three years; (4) studies with no quantitative data or that were not convertible to cases per 10,000 births; (5) studies with few cases or small samples; (6) clear region of study. In the case of two or more studies focusing on the same region, we selected the one that provided the most accurate data or the broadest range of years. We contacted the authors whose articles were not available in the database to request the full text. Only one responded and sent us the full article. The total missed articles was four.

2.3. Screening and Selection Process

A total of 30,319 sources were found through electronic database searching ( n = 30,307) and additional relevant studies were found by hand-searching ( n = 12). After duplicates were removed, a total of 17,925 articles were found. After reviewing titles and abstracts, 87 were assessed for eligibility, in accordance with the aim topics: Down Syndrome (or Trisomy 21) and Demography (or Epidemiology, or Incidence, or Birthrate). In the end, 22 full-text articles met all the inclusion criteria (clear location, quantitative data, and three or more-year period between 1960 and 2019). Figure 1 provides an outline of the search for the studies.

Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Statement flowchart of the study identification, screening, and selection process.

2.4. Quality Measurement

We developed a scale to ensure quality and consistency for our review in the last step of the selection process (eligibility). The articles were ranked with scoring criteria, and the articles were blindly reviewed. The scoring criteria were: 2 points if it clearly meets all inclusion criteria, 1 point if it meets all inclusion criteria but not clearly, and 0 points if it was not eligible. To avoid risk of bias in selection, only articles that were ranked with 2 points by both authors were included, and when there was disagreement, it was resolved by consensus. The authors agreed to 81% of the articles. Agreement on those to be included reached 86% and those to be excluded reached 71%.

2.5. Data Analysis

Our data analysis is a systematic narrative and descriptive analysis, presented in the text and tables to summarize and explain the characteristics and findings of the included studies. The descriptive analysis includes measures of central tendency (mode, median, and mean) applied to the period’s birthrates included in each study. The change in birthrate was calculated in percentages from the start point to the endpoint, classified as ascent (change positive), descent (change negative), or unclear (change near 0). The birthrate data were converted to a total per 10,000 births. We classified region, source of data (registry, record, or sample). The sources were classified as: (1) Registry (specific population-based congenital defect database), (2) Record (use of files of hospitals, laboratories, other medical centers, other institutions, or death certificates), (3) Survey (developed its own sample for the study); and the principal influence on birthrate when it was clearly recognized in the text. All data were entered and analyzed in a Microsoft Excel database (Microsoft Office Professional Plus 2016) (Microsoft Corporation, Redmond, WA, USA).

As is show in Table 1 , we included 22 studies in this systematic review. The selected studies were classified in accordance with the objectives of this review: (1) main results of the trend in birthrate, (2) main cause of this trend, and (3) main source of the study.

Description and main results of studies covered by the systematic review.

(*) Responding to principal objective, (**) responding to second objective, and (***) responding to third objective.

The references considered in this systematic review were published between 1980 and 2019, in accordance with the global spread of prenatal testing for DS. We found two studies (9%) with a start point in the 1960s, four studies (18%) with a start point in the 1970s, seven studies (32%) with a start point in the 1980s, and nine studies (41%) with a start point in the 1990s or later. Four studies (18%) had an endpoint in the 1980s, eight (36%) studies in the 1990s, and ten (45%) in 2001 or later. Regarding the span of the period studied, the mean, median, and mode are 15 years. Seven studies considered a period of less than ten years, 12 between 10 and 20 years, and two extended over 20 years. As is shown in Table 1 and Figure 2 , it is clear that the interest in demographic studies of DS increased over time.

Number of selected studies by year of start point, endpoint, and publication.

The studies selected in this systematic review come from countries (10 studies, 45%) and country subdivisions (12 studies, 55%) from Europe (8 studies, 36%), America (6 studies, 27%), Asia (5 studies, 23%), Oceania (2 studies, 9%), and Africa (one study, 5%). Regarding cultural areas, we found 14 studies from western regions (63%), five studies from eastern Asia (22%), and two studies from Latin and Caribbean countries (9%). Four studies (18%) included ethnic groups (Chinese, Malay, Indians, White, Colored, Black, and Latino as are named in the cited sources).

3.1. Trends in Demographics of Down Syndrome

Analysis of global trends showed an overall declining trend in birthrates for the total population with DS. As is shown in Figure 3 , twelve studies (55%) showed a clear decrease in birthrate, while only five studies (23%) found an increasing trend in the period studied, and five (23%) found an unclear direction.

Selected studies by percent change in birthrate, region, endpoint, and time span of the period studied. Note: The area of the bubbles is proportional to the width of the period studied.

However, this result is less clear when taking into account the time period. Following Loane [ 9 ], the trends for the most recent period (from the last 90s) showed an increasing DS birthrate, as is shown in studies from Turkey, Slovenia, Croatia, and Costa Rica [ 17 , 18 , 19 , 20 ]. Although at the same time, from 2010, we have found decreasing trends in studies from Spain, Thailand, and Cuba [ 21 , 22 , 23 ].

Regarding the studies with a broader study period (20 years or more), we found an increasing birthrate in Costa Rica [ 18 ] and a decreasing birthrate in Spain [ 21 ] and Cape Town [ 24 ], while Northern England [ 25 ] and Slovenia [ 20 ] show an unclear (but lightly increasing) trend.

3.2. Screening Tests and Prenatal Care

Global demographic trends of the DS population from 1960 to 2019 showed a consistent association between antenatal screening and a significant decrease in the incidence of DS. Ten studies [ 10 , 11 , 16 , 21 , 22 , 23 , 26 , 27 , 28 , 29 ] of the twelve that identified a descending birthrate determined that the spread of prenatal screening given by healthcare systems was the leading cause of this decrease.

Our results confirm that the demographical impact of antenatal screening has been clear since the 1980s, with the increasing availability of more sophisticated screening and less invasive prenatal diagnostic techniques [ 30 ]. The regions more affected by this trend are South Australia, Taiwan, and Spain [ 21 , 27 , 29 ].

However, in the results of studies from developed regions (Japan, Northern Netherlands, Northern England) with available prenatal screening for all pregnant women, the birthrate is not decreasing [ 25 , 31 , 32 ]. The improvement in healthcare is identified as a factor for the rising birthrate in Croatia, Costa Rica, Turkey, and Slovenia [ 17 , 18 , 19 , 20 ].

3.3. Related Variables: Maternal Age, Legal and Sociocultural Contexts

In the demography of DS, it is well recognized that a high incidence occurs with increasing maternal age. This trend is consistently confirmed in our review as the leading cause of the rising birthrate [ 18 , 25 ]. The global change of lifestyle in the last fifty years [ 31 ], with a clear tendency to postpone family planning, added to a global extension of fertility services, has resulted in an increasing pregnancy rate in patients of advanced maternal age.

Another factor influencing the rising birthrate recognized in our review is socioeconomic conditions [ 23 ], related not only with personal decisions about terminating the pregnancy but with the ability to access preventive healthcare programs and the existing legislation about medical termination of pregnancy [ 17 ].

Regarding ethnicity and sociocultural variables, we found little effect of prenatal diagnosis on birthrate in the Latino population in Los Angeles [ 16 ] and a trend to regard medical interventions on prenatal diagnosis as effected by moral sentiments in Japan [ 31 ] or religious grounds in Cape Town [ 24 ]. The variation in the prevalence of DS by ethnicity is noted, but not consistent [ 11 ].

3.4. Sources for Demographic Assessment of Down Syndrome

As shown in Table 1 , 14 of the 22 studies selected in this review (64%) used data from registries specifically designed for epidemiological monitoring of health conditions [ 19 ]. The use of registries to conduct population-based studies is especially fitting to estimate and analyze uninterrupted data with precision. The fragmentation of registries in small (administrative) territories is an added difficulty that has been found in the sources of the studies analyzed that could be solved with global registries [ 22 ]. Without population-based data about incidence, preventive politics and health care programs will not be sufficiently effective [ 17 ].

4. Discussion

This review shows whether studies provided evidence to substantiate the claim that prenatal testing decreases the DS population. Our review demonstrates a consistent association between prenatal diagnosis and birthrate, enough to explain a significant fall in the prevalence of DS.

Moreover, this trend is not persistent across regions and seems to have been more robust in the 1980s and 1990s than nowadays, although it remains evident in some countries today [ 21 , 22 ]. It seems likely the effects of antenatal diagnosis and termination of pregnancy are less than they were decades ago in some regions [ 10 , 16 , 26 , 27 , 28 ]. It is necessary to consider that in most countries, where the decreasing trend in birthrate has been reduced or even reversed, it is much lower than it was before the massive introduction of prenatal diagnostic.

The International Convention on the Rights of Persons with Disabilities (UN, 2006) established a legal framework that directly involves this situation, based on three key articles: Article 3, which establishes non-discrimination as a general principle; Article 10, which obliges States Parties to reaffirm the inherent right to life of all human beings and to take all necessary measures to guarantee this right to persons with disabilities as to others; and Article 31, which commits States Parties to collect appropriate information, including statistical and research data, to enable them to formulate and implement disability equality policies.

It is well recognized that a high incidence of DS occurs with increasing maternal age [ 33 ], so the global trend towards increasing maternal age should expand the population of DS because of an increasing birthrate. Our findings indicate that, while this trend exists, its demographic impact is limited since it is ultimately an opposite force derived from the widespread application of prenatal testing [ 21 ]. There is a clear exception to this trend in Japan, where the increasing frequency of DS has a clear weight on the increased birthrate [ 31 ].

The improvements in healthcare systems and maternity care programs, in turn, present unclear results from a demography assessment. On the one hand, improved healthcare in some developing countries has led to higher birthrates [ 18 , 19 ], which are contrasted by the expansion of prenatal testing in the same regions. In conclusion, it cannot be determined that improvements in healthcare will have an impact on the demography of DS.

In short, increasing maternal age and improved survival of children with DS have offset but not inverted, the effects of antenatal screening in the declining general birthrate. The possibility of cultural, religious, ethnic, or regional differences in screening impact and maternal age-specific rates for DS should be taken into account since they are mentioned in some of the sources used, although the influence of these variables it is not deeply studied.

We found a generalized use of specific congenital birth defect registries as the primary source of data. The high prevalence of DS as a genetic cause of intellectual disability, and the increasing interest in the demographic assessment of DS, demonstrates the global need for specific registries, completed with socioeconomic variables that allow rich comparative and long-term studies.

5. Conclusions

After five decades of prenatal diagnosis of DS, there is an intense debate whether the widening of and improvements in genetic counseling have resulted in a relative impact on the birth prevalence of DS, shown in the rising interest in demographic studies of DS showing an increasing prevalence over time.

This study is the first systematic review of empirical studies in the demography of DS. It demonstrates that there is: (1) a consistent observation of the association between prenatal diagnosis and birthrate, enough to explain a significative decrease in the prevalence of DS; (2) a somewhat rising of incidence related to increased maternal age and extension of fertility services in healthcare systems; and (3) a generalized use of specific congenital birth defect registries as the primary source of data. Also, the influence of socio-cultural and territorial variables is mostly unclear. Our findings can inform research, policy, and practice to improve the reproductive health and quality of life of the population with DS. In short, as a general response to the main objective of this review, the impact of antenatal screening on the demography of DS is evident.

Our findings can inform research, policy, and practice to improve the reproductive health, and quality of life of the population with DS, from a demographic approach, for policymaker in disability policy, organizations on disability rights, and the healthcare system.

The policymakers need to solve the conflict between protecting disability rights and improvements on prenatal care as part of healthcare. The healthcare system needs to improve communication skills based on the related variables, i.e., pregnant women’s sociodemographic position.

A critical group of interest in this frame are the organizations of people with DS and their families, which need to incorporate demographic assessment in their programs to improve the rights, social inclusion, interpersonal relationships, and material well-being [ 34 ].

The UN Committee on the Rights of Persons with disabilities has informed that the law about the abortion discriminates against the DS population. The committee has pointed about the negative perception about disability that this law contains [ 15 ]. Although it would be theoretically possible to relate the recent stabilization in the birthrate of DS in some regions to an awareness of disability discrimination, as established by the CRPD, we have no found clear evidence of it.

Future research, based on this review, should investigate how other variables and factors impact on the demography of DS. One of these factors to be investigated are gender inequalities, especially related to care. Those studies will find the intersection between gender and disability discrimination based on CRPD.

One other hand, our review lays a way to develop the demographic assessment of DS through the use of specific congenital birth defect registries as the primary source of data. The high prevalence of DS as a genetic cause of intellectual disability, and the increasing interest in the demographic assessment of DS, demonstrates the global need for specific registries, completed with socioeconomic variables that allow comparative and long-term studies.

Limitations

Our study had several limitations. The most important one is that the birthrate is a limited demographic indicator, and specifically in the population with DS, because we know that improvements in quality of life are extending the life expectancy, and so, implies an increase not contemplated in this work; we have done so because the birthrate is one of the few demographic indicators for which there are reliable data on DS, and there are very few regions in the world with reliable prevalence data of the whole population. Another critical limitation has to do with the scarcity of information that we offer about the influence of the termination of pregnancy laws that operate in each region; although there is literature on birthrate in DS and also literature on pregnancy termination legislation from a rights perspective, there are practically no sources that have used both views at the same time, so we can only talk by intuition in this area. A third limitation is the use of start point and endpoint of each series as an indicator; we have done this because several of the sources used primary figures at the first and last year, but not always in the center, making it impossible to create a standardized indicator or statistical test across each series. Fourthly, we made our search in English and Spanish, so some important references could be lost in other languages. Finally, we are aware that it would possibly be more accurate to use international registries that offer birth data of DS in several regions (such as EUROCAT), but it would not have allowed us to provide complementary information on the interest that this topic arouses in the recent literature, and the explanatory variables given in those sources, on the objectives of the study.

Acknowledgments

Special thanks to Director of INICO (University of Salamanca) who supported this research.

The PsycINFO search is an example search strategy that reflects the terms used within each database. Subtle variations in terms arose from exploded terms as these were database specific, and the formatting varied between databases. PsycINFO 1985–present. The last run was 06/08/2020.

PsycINFO search strategy.

Author Contributions

This research is part of the dissertation of doctoral student M.O.-B. with supervision by advisor A.H.-G. A.H.-G. conceptualized the review; M.O.-B. and A.H.-G. performed the search strategy and read the selected articles. M.O.-B. performed searches and extracted the data from included articles; A.H.-G. made the formal data analysis and wrote the paper’s first draft. Subsequently, all authors reviewed and edited the previous versions of the manuscript. All authors have read and agreed to the published version of the manuscript.

This systematic review was developed through access to publication databases by University of Salamanca, Spain.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Conflicts of interest.

The authors declare no conflict of interest.

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