Discussion

In this large retrospective cohort study, individuals with FND and functional somatic symptoms exhibited higher proportions of documented early-life biological vulnerability factors than matched migraine and recurrent depression cohorts, spanning inherited, congenital, perinatal, and neurodevelopmental domains, pointing to a broad early-life and developmental susceptibility rather than vulnerability confined to a single biological system. Further, there was some signal suggesting phenotype-specific patterns of early-life factors, with variation in the relative contribution of early-life biological and neurodevelopmental factors across FND and functional somatic symptom clusters. For example, connective tissue and structural musculoskeletal conditions were more common in functional motor disorder and the musculoskeletal symptom cluster, whereas neurodevelopmental diagnoses were more prominent in functional seizures and the general symptom cluster.

In both FND and functional somatic symptoms, inherited and congenital conditions were more prevalent than in matched cohorts, particularly those conditions affecting connective tissue, neuromuscular systems, and sensory organs. Our findings align with previous observations, including a recent tertiary cohort of 282 cases with FND reporting early-life medical or neurodevelopmental conditions in nearly two-thirds of patients (Tamilson et al., Reference Tamilson, Tse, Nihoyannopoulos, Yogarajah and Agrawal2026) and consistent evidence of overrepresentation of Ehlers–Danlos syndrome and hypermobility spectrum disorders among individuals with FND and functional somatic symptoms (Chen et al., Reference Chen, Olver and Kanaan2021; Chen, Castro-de-Araujo, Olver, & Kanaan, Reference Chen, Castro-de-Araujo, Olver and Kanaan2024; Fernandez et al., Reference Fernandez, Jaquet, Aubry-Rozier, Suter, Aybek and Berna2024; Landa, Mashevich, Eisenstein, & Barak, Reference Landa, Mashevich, Eisenstein and Barak2026; Margolesky, Puentes, & Espay, Reference Margolesky, Puentes and Espay2022; Nisticò et al., Reference Nisticò, Iacono, Goeta, Tedesco, Giordano, Faggioli, Priori, Gambini and Demartini2022; Wasim et al., Reference Wasim, Suddaby, Parikh, Leylachian, Ho, Guerin and So2019). The present findings align with these observations while indicating that vulnerability extends beyond hypermobility-related syndromes to encompass a broader range of conditions, including hereditary motor and sensory neuropathies, primary muscle disorders, congenital musculoskeletal and nervous system malformations, chromosomal abnormalities, and congenital sensory impairments.

These findings align with emerging evidence that FND and somatic symptom disorders may have a heritable component, with only partial overlap with depression and anxiety (Fominykh et al., Reference Fominykh, Jaholkowski, Shadrin, Koch, Luitva, Mikkelsen, Lundberg, Pedersen, Ostrowski, Erikstrup, Didriksen, Mikkelsen, Sørensen, Ullum, Bruun, Aagaard, Kowalec, Karlsson, Karlsson and Andreassen2025; Gillespie et al., Reference Gillespie, Zhu, Heath, Hickie and Martin2000). Converging genetic and epigenetic findings implicate stress-related biological pathways, particularly serotonergic and oxytocinergic systems, in susceptibility to functional and somatic symptoms (Hennings, Zill, & Rief, Reference Hennings, Zill and Rief2009; Palma-Gudiel et al., Reference Palma-Gudiel, Peralta, Deuschle, Navarro and Fañanás2019; Spagnolo et al., Reference Spagnolo, Norato, Maurer, Goldman, Hodgkinson, Horovitz and Hallett2020; Weber et al., Reference Weber, Álvarez, Stoffel, Ansede-Bermejo, Cruz, Bolt, Bühler, Carracedo and Aybek2026), and a genetic component has been reported in functional seizures (Asadi-Pooya, Hallett, Mirzaei Damabi, & Fazelian Dehkordi, Reference Asadi-Pooya, Hallett, Mirzaei Damabi and Fazelian Dehkordi2023). Broader genomic analyses indicate genetic risk is shared across psychiatric conditions rather than confined to single diagnostic categories (Grotzinger et al., Reference Grotzinger, Werme, Peyrot, Frei, de Leeuw, Bicks, Guo, Margolis, Coombes, Batzler, Pazdernik, Biernacka, Andreassen, Anttila, Børglum, Breen, Cai, Demontis, Edenberg and Smoller2026). Although genetic variation was not directly assessed in the present study, the enrichment of inherited and congenital conditions may reflect shared developmental vulnerability rather than independent causal pathways.

Perinatal factors related to impaired fetal growth and neonatal distress – particularly short gestation, low birth weight, and respiratory distress – were overrepresented in both FND and functional somatic symptoms. Short gestation and low birth weight were the most consistently increased in FND and functional somatic symptoms, along with neonatal respiratory distress. Slow fetal growth was mainly more frequent in functional somatic symptoms, whereas long gestation and high birth weight were not increased and were, in fact, less frequent in FND compared with depression. A recent case-record review similarly reported enrichment of a broad range of perinatal factors in FND (Tamilson et al., Reference Tamilson, Tse, Nihoyannopoulos, Yogarajah and Agrawal2026). These findings suggest that early disturbances in intrauterine growth and perinatal adaptation may index a broad developmental vulnerability rather than reflecting mechanisms unique to a single disorder. The underlying pathways remain unclear. Perinatal complications are established risk factors for neurodevelopmental disorders (Fitzallen, Taylor, Liley, & Bora, Reference Fitzallen, Taylor, Liley and Bora2024; Tamilson et al., Reference Tamilson, Tse, Nihoyannopoulos, Yogarajah and Agrawal2026), but may also reflect broader early medical vulnerability and shape caregiving contexts and illness-related experiences (Turkel & Pao, Reference Turkel and Pao2007). In contrast to connective tissue and neurodevelopmental associations, perinatal influences have not previously been systematically examined in FND or functional somatic symptoms. However, low birth weight, impaired fetal growth, and perinatal hypoxia have been linked to a range of neurodevelopmental and psychiatric outcomes, including ASD, schizophrenia, ADHD, epilepsy, and affective conditions (Giannopoulou, Pagida, Briana, & Panayotacopoulou, Reference Giannopoulou, Pagida, Briana and Panayotacopoulou2018; Kong et al., Reference Kong, Chen, Liang, Forsell, Gissler and Lavebratt2022; Sun et al., Reference Sun, Vestergaard, Pedersen, Christensen, Basso and Olsen2008; Von Beckerath et al., Reference Von Beckerath, Kollmann, Rotky-Fast, Karpf, Lang and Klaritsch2013; Wang, Geng, Liu, & Zhang, Reference Wang, Geng, Liu and Zhang2017), each of which may independently confer increased vulnerability or contribute to susceptibility to later functional symptoms.

The present study confirms the relevance of neurodevelopmental disorders in both FND and functional somatic symptoms, consistent with prior literature. In previous work using the TriNetX platform, increased prevalence of ASD in individuals with FND was reported, with ADHD particularly elevated in those with co-occurring FND and ASD (Smythe et al., Reference Smythe, Asan, Nicholson, Happé and Edwards2025). The current study replicates and extends these findings to matched control cohorts and demonstrates that neurodevelopmental disorders are also enriched in functional somatic symptoms. A recent case-record review from a tertiary outpatient UK-based neuropsychiatry clinic similarly reported neurodevelopmental conditions in 32% of FND patients, including ASD in 12.1% and ADHD in 10.3% (Tamilson et al., Reference Tamilson, Tse, Nihoyannopoulos, Yogarajah and Agrawal2026). Although not directly comparable due to differences in study design, we observed increased proportions of most neurodevelopmental conditions in FND compared with both control groups (ORs = 1.9–5.4), except for ADHD, which was slightly more prevalent in depression, possibly reflecting reported comorbidity between ADHD and depression (Katzman et al., Reference Katzman, Bilkey, Chokka, Fallu and Klassen2017). While prior literature has reported increased frequencies of ASD (González-Herrero et al., Reference González-Herrero, Morgante, Pagonabarraga, Stanton and Edwards2022; Nisticò et al., Reference Nisticò, Goeta, Iacono, Tedesco, Giordano, Faggioli, Priori, Gambini and Demartini2022; Tamilson et al., Reference Tamilson, Poole and Agrawal2024) and ADHD (Staunton, Rudrappa, & Rathnaiah, Reference Staunton, Rudrappa and Rathnaiah2024) in FND and higher levels of autistic traits in functional somatic symptom populations (Carpita et al., Reference Carpita, Nardi, Tognini, Poli, Amatori, Cremone, Pini and Dell’Osso2024), our findings point to a broader neurodevelopmental signal beyond specific diagnostic categories. A symptom cluster-specific pattern also emerged. Epidemiological data indicate that intellectual disability is overrepresented in functional seizure cohorts relative to the general population (Rawlings, Novakova, Beail, & Reuber, Reference Rawlings, Novakova, Beail and Reuber2021). Neurodevelopmental conditions have been linked to alterations in cortical excitability, increasing vulnerability to epileptic seizures (Takarae & Sweeney, Reference Takarae and Sweeney2017), which may in turn serve as a scaffold for the development of functional seizures. Developmental language disorders have consistently been associated with impairments in motor coordination, praxis, and sequencing, features reflecting alterations in motor control (Kisjes et al., Reference Kisjes, van der Schaaf, Noordstar, Mombarg, Gerrits, Wijnen and Luinge2025). Our findings showed a similar pattern, with communication disorders enriched in functional motor disorder.

Although early-life vulnerability was evident across both diagnostic groups, its distribution was not uniform. Subgroup analyses showed phenotype-specific vulnerability profiles across both FND and functional somatic symptom presentations. Within FND, motor presentations were more strongly associated with muscle, connective tissue, and musculoskeletal conditions, whereas functional seizures were more strongly linked to neurodevelopmental and chromosomal abnormality factors, consistent with prior reports of increased autism diagnosis in functional seizures (McWilliams et al., Reference McWilliams, Reilly, Gupta, Hadji-Michael, Srinivasan and Heyman2019). Functional somatic symptom clusters showed partially distinct vulnerability profiles. The musculoskeletal symptom cluster was most strongly associated with connective tissue and structural musculoskeletal conditions, while the gastrointestinal symptom cluster showed a broader profile, including primary muscle disorders, chromosomal abnormalities, short gestation, and selected neurodevelopmental conditions, with a similar pattern also associated with the general symptom cluster. Structural gastrointestinal abnormalities may also have been present; however, these were not assessed specifically, as increased detection could reflect symptom-driven investigations rather than etiological relevance. In contrast, cardiopulmonary and genitourinary clusters exhibited comparatively fewer cluster-specific associations. It is tempting to speculate on potential mechanisms of the apparent phenotypic clustering of vulnerability profiles; however, in our view, this needs more detailed research with cohorts who can be more precisely defined clinically.

These findings suggest that early-life biological vulnerability may influence the stability of systems underpinning bodily perception and motor control. Conditions affecting connective tissue and proprioceptive pathways may reduce sensory precision and reliability; neuromuscular factors may interfere with motor integration and sensorimotor calibration. Sensory impairments may decrease exteroceptive consistency. Perinatal and neurodevelopmental factors may shape both peripheral sensory and motor systems and the central integrative mechanisms during sensitive periods of brain maturation (Meredith, Reference Meredith2015), influencing cognitive and emotional development directly and indirectly through adverse social experiences associated with developmental differences. Subtle sensorimotor network alterations have been described in structural neuroimaging studies of FND and functional somatic symptoms (Bègue, Adams, Stone, & Perez, Reference Bègue, Adams, Stone and Perez2019). Although these associative data preclude mechanistic conclusions, early differences in sensory, motor, and integrative processing may influence how bodily signals are stabilized over time. If sensory inputs are less reliable or inconsistently integrated during development, greater reliance on higher-level expectations may be required to maintain coherent perception and action. While adaptive, such compensatory weighting could confer vulnerability under stress. This is consistent with the predictive processing model of functional symptoms, which proposes that symptoms emerge when prior expectations exert disproportionate influence over ambiguous or imprecise sensory signals, contributing to symptom persistence even without structural damage (Edwards et al., Reference Edwards, Adams, Brown, Pareés and Friston2012; Lehnen, Henningsen, Ramaioli, & Glasauer, Reference Lehnen, Henningsen, Ramaioli and Glasauer2018). Overall, the evidence presented here supports moving beyond the psychogenic–organic dichotomy toward a vulnerability–resilience model in which early-life biological factors shape the stability of brain–body regulation systems and influence how these systems respond to later physical, psychological, and social stressors. Such vulnerability may also emerge through acquired disruption of these same systems later in life.

This study extends previous work by analyzing a large, multi-institutional EHR dataset to systematically assess early-life biological vulnerability in FND and functional somatic symptoms. This scale allowed us to examine multiple vulnerability domains and also supported comparisons across phenotypes. For example, evidence on connective tissue involvement – one of the most consistently reported associations – comes mainly from small studies of single syndromes (Chen et al., Reference Chen, Olver and Kanaan2021), while the present study adds size, matched comparators, and a wider range of functional presentations. Migraine and depression were included as comparators because of their partially overlapping risk profiles and epidemiology with FND and functional somatic symptoms, meaning that associations persisting despite shared risk profiles are less likely to reflect vulnerability to neurological or affective illness alone. Although excluding comorbid cases showed a similar pattern of results, shared pathophysiology may still contribute to the observed associations. Migraine itself is associated with functional somatic symptoms such as chronic fatigue syndrome and fibromyalgia (Stone et al., Reference Stone, Coebergh, Khoja, Butler, Nicholson and Dodick2025), as well as with autism (Mohammad et al., Reference Mohammad, Bussu, Rukh, Schiöth and Mwinyi2025). A further strength is the robustness of the primary findings across three further sensitivity analyses. The primary findings were robust to diagnostic miscoding (restricting to individuals with two temporally distinct diagnoses), comorbidity burden (additionally matching on common medical comorbidities), and ascertainment bias linked to diagnostic work-up (restricting vulnerability factors to those recorded more than 1 year before the index diagnosis).

Our findings must be interpreted in light of limitations inherent to retrospective EHR-based research. Diagnostic coding limits clinical granularity, with early-life conditions often under-recorded or variably documented. Combined hypermobility syndrome and EDS prevalence in our FND cohort (1.4%) was far below general-population estimates (17.2%) (Jari & Alaei, Reference Jari and Alaei2026), likely reflecting reported under-coding, alongside possible inconsistent distinction between the two diagnoses (Demmler et al., Reference Demmler, Atkinson, Reinhold, Choy, Lyons and Brophy2019). Similarly, ASD prevalence in FND has been estimated at around 10% (Vickers et al., Reference Vickers, Menhinnitt, Choi, Malacova, Eriksson, Churchill, Oddy, Boon, Randall, Braun, Taggart, Marsh and Pun2025), but was lower here, consistent with established under-recording – up to 9 out of 10 adults with autism over 50 remain undiagnosed (O’Nions et al., Reference O’Nions, Petersen, Buckman, Charlton, Cooper, Corbett, Happé, Manthorpe, Richards, Saunders, Zanker, Mandy and Stott2023). It was also slightly lower than in a previous TriNetX FND cohort – 1.7% versus 2.3% (Smythe et al., Reference Smythe, Asan, Nicholson, Happé and Edwards2025), reflecting differences in coding, age and time restrictions, and extraction date, as the database is continuously updated. Conversely, growing awareness of FND–hypermobility and FND–autism associations may have prompted more active screening in FND cohorts, potentially inflating associations through differential ascertainment, particularly as these conditions have been variably recognized across birth cohorts and diagnostic eras. Diagnostic workup may differ across phenotypes, affecting which comorbid conditions are detected. More severe symptoms may also increase healthcare contact and comorbidity ascertainment across all cohorts, though many vulnerability factors (e.g. birth weight) are unlikely to depend on utilization alone. Nevertheless, consistent group differences for more objectively coded factors offer some reassurance against systematic coding artefact.

ICD-based diagnoses are imperfect proxies of biological vulnerability, reducing multidimensional developmental factors to discrete codes, which cannot capture severity, subclinical traits, or timing of onset. Diagnostic imprecision may be particularly relevant for FND, variably coded in routine datasets (Herbert et al., Reference Herbert, Kim, Hassan, Wilkinson-Smith and Waugh2021) and for F45 diagnoses applied inconsistently in practice. While misdiagnosis of FND appears to be rare (Stone et al., Reference Stone, Smyth, Carson, Lewis, Prescott, Warlow and Sharpe2005), diagnostic overlap or misclassification between FND and F45-coded functional somatic symptoms cannot be excluded. In the FND phenotype comparison, cohorts were designed to be mutually exclusive, with the aim of reflecting only stable presentations, given that FND phenotypes may evolve over time (Tomić et al., Reference Tomić, Ječmenica Lukić, Petrović, Svetel, Dragašević Mišković, Kresojević, Marković and Kostić2020). However, a change in phenotype may not always be reflected in coding, meaning some mixed or evolving presentations may still be present within the cohorts.

The same applies to the comparator groups. For example, our migraine definition does not distinguish episodic from chronic forms, which may differ mechanistically in their relationship to functional symptoms. The analyzed cohorts may therefore represent individuals with formal diagnostic coding rather than the full clinical spectrum. Further, the F45 symptom clusters represent pragmatic, EHR-derived symptom groupings rather than clinically validated functional somatic symptom subtypes. Their classification may be imprecise, as the symptom codes used to define clusters may reflect structural, inflammatory, or other comorbid conditions rather than functional symptoms, despite their temporal proximity to the F45 diagnosis.

Finally, the early-life factors examined here are conceptualized as vulnerability markers rather than independent risk factors, as shared upstream vulnerability may render them developmental correlates rather than causal antecedents. The distinction between biological and psychosocial domains is likewise a simplification, as biological factors often carry psychosocial consequences.

In conclusion, this study provides a large-scale, systematic demonstration that inherited conditions and early-life biological vulnerability are enriched in both FND and functional somatic symptoms, extending beyond previously reported associations. The observed associations spanned multiple biological domains, indicating broad early-life susceptibility alongside more phenotype-specific vulnerability profiles related to distinct clinical presentations. Future longitudinal, prospectively designed large-scale studies are needed to clarify how different vulnerability profiles influence symptom trajectories, phenotype expression, and individual outcomes. In parallel, mechanistic work linking early-life vulnerability to brain–body regulation may help explain why similar vulnerabilities give rise to different clinical outcomes across individuals and phenotypes, informing more integrated models of functional disorders.