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

This cross-sectional observational study investigates the clinical and biochemical relationship between Attention-Deficit/Hyperactivity Disorder (ADHD) and Benign Joint Hypermobility Syndrome (BJHS) in pediatric patients. The primary objective is to evaluate the prevalence of BJHS in children diagnosed with ADHD and compare serum prolidase levels with those of healthy controls. The study also explores whether the severity of ADHD symptoms correlates with serum prolidase activity. Clinical assessments include the Conners Parent Rating Scale, Beighton Score, and serum prolidase measurement using ELISA. This research aims to provide new insights into the potential connective tissue-neurodevelopmental link and contribute to early screening frameworks for children with ADHD.

Study Overview

• Status: Completed
• Conditions: ADHD; ADHD - Combined Type; ADHD - Inattentive Type; ADHD - Attention Deficit Disorder With Hyperactivity; Benign Joint Hypermobility Syndrome

Detailed Description

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:

1. determine the frequency and severity of joint hypermobility in children diagnosed with ADHD,
2. compare Beighton Scores between ADHD and healthy control groups,
3. measure and compare serum prolidase enzyme levels between both groups, and
4. 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.

• Study Type: Observational
• Enrollment (Actual): 171

Contacts and Locations

Study Locations

• Turkey (Türkiye)
  • Muratpaşa
    • Antalya, Muratpaşa, Turkey (Türkiye), 07100
      • Antalya Training and Research Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child
• Accepts Healthy Volunteers: Yes

• Sampling Method: Non-Probability Sample

Study Population

The study population consisted of children aged 6 to 12 years, including 86 patients diagnosed with Attention-Deficit/Hyperactivity Disorder (ADHD) according to DSM-5 criteria and 85 age- and sex-matched healthy controls. Patients were recruited from the Child and Adolescent Psychiatry outpatient clinic of Antalya Training and Research Hospital. Control subjects were selected from the general pediatric outpatient department. All participants were evaluated for ADHD symptom severity, joint hypermobility, and serum prolidase levels.

Description

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

Study Plan

How is the study designed?

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort
Group 1 Name: ADHD Group Type: Observational Cohort; Children aged 6 to 12 years who were clinically diagnosed with Attention-Deficit/Hyperactivity Disorder (ADHD) according to DSM-5 criteria. Participants in this cohort were recruited from the Child and Adolescent Psychiatry outpatient clinic of Antalya Training and Research Hospital. Each child underwent a detailed clinical evaluation including the Conners' Parent Rating Scale-Revised: Short Form (CPRS-R:S) to determine ADHD symptom severity and subtype. Joint hypermobility was assessed using the Beighton Score, and venous blood samples were collected to measure serum prolidase enzyme activity using ELISA. No therapeutic intervention was applied; this is a non-interventional observational group.
Group 2 Name: Control Group Type: Observational Cohort; This group consisted of age- and sex-matched healthy children between 6 and 12 years of age with no history of psychiatric, neurological, or systemic illness. Control participants were selected from the general pediatric outpatient population and underwent the same evaluations as the ADHD group. These included the Conners' Parent Rating Scale-Revised: Short Form (CPRS-R:S), Beighton Score assessment for joint hypermobility, and serum prolidase measurement via ELISA. The purpose of this group was to provide a baseline comparison for clinical and biochemical parameters without any intervention applied.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of comorbid Benign Joint Hypermobility Syndrome (BJHS) in children with ADHD	The primary outcome is to evaluate the incidence of Benign Joint Hypermobility Syndrome (BJHS) among children diagnosed with Attention Deficit Hyperactivity Disorder (ADHD), compared to healthy controls. Diagnosis of BJHS will be based on a Beighton score ≥5 and clinical evaluation.	At enrollment (single visit)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Beighton Score for Joint Hypermobility	Generalized joint hypermobility will be assessed using the Beighton scoring system (range: 0-9), with a cutoff value of ≥5/9 as a diagnostic threshold. The total Beighton scores of children with ADHD (ages 6-12) will be compared to healthy controls.	At enrollment (single visit)
Serum Prolidase Level	Fasting venous blood samples will be collected from all participants and serum prolidase levels will be measured using ELISA. Prolidase enzyme activity (U/L) will be compared between the ADHD group and healthy controls.	At enrollment (single visit)
Sociodemographic Characteristics	Sociodemographic data including age (in years), sex, height (in cm), weight (in kg), and socioeconomic status (classified as 0: low, 1: moderate, 2: high) will be collected and compared between groups.	At enrollment

Collaborators and Investigators

• Sponsor: Antalya Training and Research Hospital

Study record dates

Study Major Dates

• Study Start (Actual): April 1, 2025
• Primary Completion (Actual): September 1, 2025
• Study Completion (Actual): October 11, 2025

Study Registration Dates

• First Submitted: August 16, 2025
• First Submitted That Met QC Criteria: June 17, 2026
• First Posted (Actual): June 23, 2026

Study Record Updates

• Last Update Posted (Actual): June 23, 2026
• Last Update Submitted That Met QC Criteria: June 17, 2026
• Last Verified: May 1, 2026

More Information

Terms related to this study

• Keywords: adhd; prolidase; joint hypermobility; bjhs; beighton score
• Additional Relevant MeSH Terms: Musculoskeletal Diseases; Mental Disorders; Joint Diseases; Neurodevelopmental Disorders; Attention Deficit and Disruptive Behavior Disorders; Attention Deficit Disorder with Hyperactivity; Joint Instability
• Other Study ID Numbers: 130220253/2

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Individual participant data that underlie the results reported in this study (including de-identified demographic, clinical, and biochemical data such as age, sex, Conners' scores, Beighton scores, and serum prolidase levels) will be shared upon reasonable request to the corresponding investigator.
• IPD Sharing Time Frame: IPD and supporting documents will be available upon reasonable request after publication of study results. Requests can be submitted via email to the principal investigator. All shared data will be de-identified.
• IPD Sharing Access Criteria: Qualified researchers affiliated with academic or research institutions may request access to de-identified individual participant data (IPD) and supporting documents (e.g., study protocol, statistical analysis plan) by contacting the principal investigator via email. All requests will be reviewed and must include a data use agreement. Data will be provided electronically under secure conditions, only for non-commercial scientific purposes.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No