Evaluation of Benign Joint Hypermobility and Serum Prolidase Levels in Children Diagnosed With Attention-Deficit/Hyperactivity Disorder (ADHD) Compared to Healthy Controls

Attention-Deficit/Hyperactivity Disorder (ADHD) is a prevalent neurodevelopmental disorder characterized by inattention, hyperactivity, and impulsivity, often presenting in early childhood. Although traditionally viewed as a purely behavioral and neurochemical condition, increasing evidence suggests a potential overlap with systemic and somatic findings, including those related to connective tissue disorders. One such condition is Benign Joint Hypermobility Syndrome (BJHS), a clinical entity involving increased joint flexibility due to altered collagen structure or metabolism.

Recent hypotheses have proposed a shared pathophysiological basis between neurodevelopmental disorders and connective tissue abnormalities, possibly mediated by enzymatic and inflammatory pathways. Prolidase is a cytosolic exopeptidase that plays a key role in collagen turnover and proline recycling. It has been implicated in various connective tissue disorders and may also influence neuroinflammatory processes. Thus, prolidase activity may serve as a biochemical bridge between BJHS and ADHD.

This cross-sectional observational study was conducted to investigate the clinical and biochemical associations between ADHD and BJHS in a pediatric population. Specifically, the study aimed to:

• determine the frequency and severity of joint hypermobility in children diagnosed with ADHD,
• compare Beighton Scores between ADHD and healthy control groups,
• measure and compare serum prolidase enzyme levels between both groups, and
• assess whether prolidase activity and hypermobility scores correlate with ADHD symptom severity and subtype (predominantly inattentive, hyperactive/impulsive, or combined presentation).

A total of 171 children aged 6 to 12 years participated in the study: 86 with a clinical diagnosis of ADHD (based on DSM-5 criteria) and 85 age- and sex-matched healthy controls without psychiatric or systemic illnesses. Participants in the ADHD group were recruited from the Child and Adolescent Psychiatry Department of Antalya Training and Research Hospital. Control subjects were selected from the general pediatric outpatient population, ensuring the absence of known neurodevelopmental or rheumatological disorders.

All participants underwent a standardized assessment battery. ADHD symptom severity was quantified using the Conners' Parent Rating Scale-Revised: Short Form (CPRS-R:S), which also allowed classification into ADHD subtypes. Joint hypermobility was assessed using the Beighton scoring system, with a threshold score ≥4 indicating hypermobility. Sociodemographic data were collected via structured interviews with caregivers. Venous blood samples were obtained to determine serum prolidase levels, analyzed using a validated ELISA method.

Data were statistically analyzed to evaluate group differences in Beighton Scores and prolidase levels, as well as correlations between biochemical markers, ADHD severity scores, and ADHD subtype classifications. Subgroup analyses were also conducted to assess whether prolidase activity or joint hypermobility was more strongly associated with specific ADHD presentations (e.g., inattentive vs. combined type).

By integrating clinical, physical, and biochemical data, this study seeks to offer a multidimensional perspective on ADHD, moving beyond traditional neurocognitive models. The findings may support the development of new screening and diagnostic strategies, particularly for pediatric patients who present with both behavioral symptoms and physical signs such as joint hypermobility. Additionally, this research may help identify candidate biomarkers for early intervention and interdisciplinary assessment in child psychiatry and pediatric rehabilitation settings.

Inclusion criteria

• Children aged between 6 and 12 years
• ADHD diagnosis based on DSM-5 criteria (for patient group)
• Healthy children with no known psychiatric or systemic disease (for control group)
• Willingness of the parents or legal guardians to participate and provide informed consent
• Ability to complete the required clinical assessments (CPRS-R:S, Beighton Score, blood sample)

Exclusion criteria

• Presence of chronic systemic diseases (e.g., autoimmune disorders, connective tissue diseases, metabolic syndromes)
• History of neurodegenerative or severe neurological disorders Intellectual disability or autism spectrum disorder diagnosis
• Use of medications that may affect prolidase enzyme activity (e.g., corticosteroids, immunosuppressants)
• Any orthopedic or musculoskeletal condition interfering with Beighton assessment
• Incomplete clinical or laboratory data
• Refusal to participate or lack of parental consent