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Currently available screening instruments for evaluation of individuals with intellectual disabilities do not capture all the complications associated with Down Syndrome (DS). Here, we examined age and gender-specific variability revolving around major challenges related to ophthalmologic and auditory health, social integration, daily life, and behavioral problems in 468 (age: 2–84 years) individuals with DS living in all eight divisions of Bangladesh. More than half of the children presented with significant difficulty in walking or other targeted movements compared with 37.9% of adolescents (p = 0.03). Nearly 70% of children exhibited communication difficulties, particularly revolving around the understanding of speech, comprehending or learning tasks or new materials, and in expressing thoughts in words or behaviors (p = 0.003–0.006). Uncontrolled urination was frequent and predominantly found among children (p = 0.04). No significant differences were present in females vs. males except for concern about physical appearance (females: 58.5% vs. males: 47.5%; p = 0.02). The severity of DS was associated with intellectual performance, communication difficulties, and self-sufficiency (i.e., uncontrolled micturition or bowel movements) but not with psychotic, ophthalmologic, auditory, or motor skills-related problems. Increased awareness of DS phenotypic profiles among professionals and caregivers can foster earlier detection and counselling and help formulate appropriate interventions to reduce long-term sequelae and enhance cognitive and behavioral developmental outcomes.