PACS1-related neurodevelopmental disorder (PACS1-NDD, Schuurs-Hoeijmakers syndrome) is an ultra-rare disorder predominantly caused by the recurrent de novo PACS1 p.(Arg203Trp) variant, characterised by intellectual disability, prominent speech and language impairment, epilepsy, behavioural difficulties and multisystem involvement across the lifespan. No internationally agreed recommendations exist for its clinical management or longitudinal surveillance, and no standardised outcomes have been defined for therapeutic studies. This has become pressing with the registration of the first PACS1-directed therapeutic study (NCT07474298).
This international, web-based, two-round Delphi study aims to establish: consensus-based recommendations for diagnosis, clinical assessment, management and surveillance; a lifespan Core Outcome Set for future therapeutic studies; domain-specific outcomes to be assessed when clinically relevant; and the potential role of EEG and molecular/epigenetic measures as candidate objective outcomes or biomarkers.
The panel comprises international clinicians and researchers with documented PACS1-NDD experience, covering paediatric and adult populations. Candidate items were derived from the published literature and defined jointly with the scientific committee of PACS1 Italia, the Italian patient association. Items are rated on a 9-point scale. Consensus in is defined a priori as =70% of respondents scoring 7–9 with <15% scoring 1–3; consensus out as the reverse. Unresolved items are carried to round two with anonymised aggregated feedback. The COS is defined at the level of outcome domains; selection of measurement instruments is outside the present scope. Development and reporting follow COS-STAD and COS-STAR.
A search of the COMET database (conducted on 21th September 2026)[DATE]) identified no registered or published core outcome set for PACS1-related neurodevelopmental disorder. We considered the following potentially relevant work:
1) Intellectual disability. Records classified under intellectual disability address relationships and sex education, and challenging behaviour. Both concern specific interventions or behavioural domains in heterogeneous populations rather than clinical or therapeutic outcome measurement in a genetically defined disorder.
2) Epilepsy. Core outcome sets have been developed for rolandic epilepsy (CHOICE; Crudgington et al., Epilepsia 2019), for childhood epilepsy treated with ketogenic diet therapy (CORE-KDT; Epilepsia 2023), and for infantile spasms and West syndrome (West Delphi group; Epilepsia 2004). These are relevant to the seizure domain, but in PACS1-NDD epilepsy affects approximately half of individuals and is not the defining feature, so an epilepsy-centred outcome set would not capture the principal clinical burden.
3) Monogenic neurodevelopmental disorders. A preliminary core set of patient- and caregiver-relevant outcomes has been developed for Dravet syndrome (Nabbout et al., Epilepsy Behav 2018), identifying seizures, expressive and receptive communication, daily activities, and caregiver social functioning. This is conceptually the closest precedent and supports the centrality of communication in monogenic neurodevelopmental disorders, but it is disorder-specific, seizure-dominated, and restricted to childhood. No core outcome set for therapeutic studies was identified for Angelman syndrome or SYNGAP1-related disorder. For Rett syndrome, a core set has been developed through an international networked database (Grillo et al., Hum Mutat 2012), which harmonises a core clinical and genetic dataset across centres to support natural history and genotype–phenotype studies, clinical trial recruitment, and quality of care. Its focus is standardised data collection rather than the prioritisation of outcome domains for evaluating therapeutic effect, and it is specific to Rett syndrome; it nonetheless provides a useful precedent for harmonised multicentre data collection in a monogenic neurodevelopmental disorder.
Rationale for a new COS. PACS1-NDD has a distinct profile not addressed by existing outcome sets: communication and adaptive functioning are disproportionately affected; epilepsy is frequent but not universal; multisystem involvement is substantial; and the condition is lifelong, requiring outcomes relevant to adolescents and adults. The disorder's molecular homogeneity and the registration of the first PACS1-directed therapeutic study (NCT07474298) make standardised outcome selection timely. We therefore propose a disorder-specific lifespan COS organised into universal core domains and phenotype-dependent outcomes, which may also inform outcome selection in other monogenic neurodevelopmental disorders.
Dr. Diego Lopergolo, Md, PhD
Department of Medicine, Surgery and Neurosciences,
University of Siena,
Siena, Italy
Disease Category: Genetic disorders
Disease Name: PACS1-related neurodevelopmental disorder
Age Range: 0 - 99
Sex: Either
Nature of Intervention: Any
- Clinical experts
- Patient/ support group representatives
- Researchers
- COS for clinical trials or clinical research
- COS for practice
- Delphi process
International, web-based, two-round e-Delphi consensus study. Candidate items were derived from the published PACS1-NDD literature and defined jointly with the scientific committee of the PACS1 Italian patient association. The questionnaire comprises six sections: diagnosis and baseline assessment; clinical management and surveillance; candidate universal core outcome domains; domain-specific outcomes relevant to individuals with specific manifestations; EEG and molecular/epigenetic measures; and open-text suggestions.
The panel comprises clinicians and researchers with documented PACS1-NDD experience, purposively sampled to cover paediatric and adult populations and relevant disciplines. Items are rated on a 9-point scale. Consensus in is defined a priori as =70% scoring 7–9 and <15% scoring 1–3; consensus out as =70% scoring 1–3 and <15% scoring 7–9. Items without consensus, and new items suggested in Round 1, are re-rated in Round 2 after participants receive anonymised aggregated feedback and their own previous score. Items without consensus after Round 2 are reported as such; no further round or consensus meeting is planned.
The COS is defined at the level of outcome domains; selection of measurement instruments will be addressed in subsequent work. Development and reporting follow COS-STAD and COS-STAR.