Developmental Influences on Medically Unexplained Symptoms

Background: Medically unexplained (or ‘functional’) symptoms (MUS) are physical symptoms that prompt the sufferer to seek healthcare but remain unexplained after an appropriate medical evaluation. Examples of MUS also occur in veterinary medicine. For example, domestic cats suffer a syndrome comparable to interstitial cystitis, a chronic pelvic pain syndrome of humans. Method: Review of current evidence suggests the hypothesis that developmental factors may play a role in some cases of MUS. Maternal perception of a threatening environment may be transmitted to the fetus when hormones cross the placenta and affect fetal physiology, effectively ‘programming’ the fetal stress response system and associated behaviors toward enhanced vigilance. After birth, intense stress responses in the individual may result in similar vulnerability, which may be unmasked by subsequent stressors. Results: Epigenetic modulation of gene expression (EMGEX) appears to play a central role in creation of this ‘survival phenotype’. The recent development of techniques to identify the presence of EMGEX provides new tools to investigate these questions, and drugs and other interventions that may reverse EMGEX are also under active investigation. Conclusion: Viewing MUS from the perspective of underlying developmental influences involving EMGEX that affect function of a variety of organs based on familial (genetic and environmental) predispositions rather than from the traditional viewpoint of isolated organ-originating diseases has at least two important implications: it provides a parsimonious explanation for findings heretofore difficult to reconcile, and it opens whole new areas of investigation into causes and treatments for this class of disorders.