In Madonna Blyth, Collins wanted to represent "the character of a ’Deaf Mute’ as literally as possible according to nature," in contrast to the deaf characters featured in nineteenth-century stage melodramas. The novel offers a substantial "case history" of her accidental deafening, diagnosis, and treatment, based on religious writer John Kitto’s The Lost Senses (1845), a popular semi-autobiographical account of deafness and blindness. Like Kitto, Madonna is subjected to a host of invasive treatments and diagnosed as having a paralyzed auditory nerve produced by the shock of the impact. The particularities of "deaf behavior" Collins assigns her are partly drawn from Kitto’s book.

Collins’s construction of a deaf woman as desirable and desiring was radical for his time, as was his development of her case history. The novel’s discussion of Lavinia Blyth’s spinal disease is also more clinically detailed than most Victorian representations of illness and disability.

The adoption narrative is a significant narrative element, and memorably captures the Blyths’ fervor for Madonna and their anxiety about losing her. Collins portrays this family built through adoption as an idyllic triad, especially in contrast to the two miserable biological families in the novel. For twentieth-century readers, Hide and Seek highlights the ethical issues surrounding quick adoptions of disabled and other children perceived as "available" to anyone willing to take on their guardianship. This issue recurs in Dickens’s Christmas story "Doctor Marigold."