Increasing numbers of children with rare disorders now have access to therapeutic choices made possible by developments in genetic and pharmacological technology and pediatric care. Health-Related Quality of Life (HRQoL) and mental health of this impaired group and their siblings are of rising importance, despite the fact that present treatment choices are mostly palliative in nature. The population of interest in the research consists of children and adolescents who are technologically reliant and suffer from rare diseases. Children’s HRQoL was evaluated using the DISABKIDS (DCGM-37) and KIDSCREEN-27 in a cross-sectional observational design, and mental health was evaluated using the Strengths and Difficulties Questionnaire (SDQ) by the children, their parents, and their siblings. The findings from the study group were compared to benchmark statistics. Results on practically all HRQoL subscales for affected children were significantly poorer than average, according to reports from both children and their parents. When looking at mental health from the parents’ perspective, more subscales were considerably affected than when looking through the eyes of the children. In regards to their mental health, siblings did not exhibit any decrease in HRQoL and actually displayed much fewer behavioral disorders and more prosocial conduct than the average. Human resource quality of life (HRQoL) and mental health appear to be especially compromised in children and adolescents with uncommon disorders. Social skills, prosocial behavior, and positive peer relationships may all be primary targets of intervention.