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).

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).

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).

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).

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).

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.

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.

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).

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).

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.