Kirsten Furley

Developmental regression during childhood is inconsistently defined and measured, resulting in delayed diagnostic discovery and intervention. This study aimed to examine published definitions and measures for developmental regression. A comprehensive search strategy was applied to Medline, Embase, Cochrane, and PsycINFO databases. Reviewers independently screened relevant studies according to the Preferred Reporting Items for Systematic reviews . The number and percentages of definition use, their primary features, and measures were reported. Of 19,099 potential publications, 157 were included. Thematic analysis identified four condition groups: Neurodevelopmental disorders ( n = 118); Progressive neurodegenerative conditions ( n = 17); Developmental epileptic encephalopathies ( n = 8); and Genetic conditions ( n = 14). Most studies ( n = 124, 79.0%) used an operational definition, and most specified types of skills lost ( n = 147, 93.6%). Age of onset was specified in 67.5% ( n = 106), and duration was specified in 34.4% ( n = 54). Measures designed to specifically assess developmental regression were infrequently used ( n = 5, 3.2%). We concluded that developmental regression is inconsistently defined and measured. A consistent approach is vital to ensure that all children are identified as early as possible. This will allow timely diagnostic discovery, enhance research rigor, and promote the collaboration that is needed to advance our understanding of causal mechanisms and effective interventions for affected children and their families.

Aim: To reach an agreed approach to define developmental regression, to improve understanding of aetiology, prevalence, and timing of investigations, and provide standardized and consistent care. Method: Developmental regression is a symptom of several developmental, epileptic, genetic, and metabolic conditions (e.g. autism, Rett syndrome, childhood dementias, and Landau–Kleffner syndrome). An expert interdisciplinary clinician panel reviewed the literature for existing definitions and formulated a survey using the Delphi method. Health care clinician perspectives on key elements required for a definition were sought. The survey was completed over two rounds and consensus was defined as a minimum of 70% agreement. Results: Of the 76 clinicians who completed the first‐round survey, 41 completed the second round (54%). Consensus was reached on the following definition. Developmental regression refers to: (1) skill(s) loss experienced during childhood lasting a minimum of 4 weeks, and (2) occurring in at least 1 of 6 developmental domains (verbal communication, nonverbal communication, functional motor skills, cognition, social skills, and self‐help skills). Interpretation: A working definition of developmental regression is proposed. The intention is that this definition will undergo improvements through use and evaluation to increase its utility and uptake in clinical care and research.

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This systematic review evaluates the diagnostic yield of investigations requested for children with developmental regression. Online databases MEDLINE, EMBASE, CINAHL, PsycINFO, Cochrane were searched to identify published records that reported a diagnostic yield for children with developmental regression. Random effects meta-analyses were performed using R software with meta package. Our search identified 11,283 published records, of which 347 were assessed for eligibility, and 15 (596 children) were included in the final systematic review and meta-analysis. Subgroup analysis assessed the diagnostic yield for investigating children with different presentations and developmental regression. Diagnostic yield results were 68% for children with neurological symptoms (two records, six children, 95%CI 32–100) and children with epileptic symptoms (two records, 56 children, 95%CI 15–100); 40% for children with neurodevelopmental delay (six records, 294 children, 95%CI 3–78); 9% for autistic children (three records, 138 children, 95%CI 0–26). Pooled analysis could not be completed for metabolic (one record, 29 children) or genetic presentations (one record, 73 children). The diagnostic yield for genetic/genomic investigations (six records, 142 children, 95%CI, 47–92) was 70%, compared with 28% for metabolic (five records, 286 children, 95%CI 0–64), 13% for neurophysiological (two records, 127 children, 95%CI 0–39) and 6% for neuroimaging (two records, 41 children, 95%CI 0–20). Investigations for children with developmental regression and neurological or epileptic symptoms resulted in the highest diagnostic yield. These results are clinically meaningful and will inform future research to advance towards an agreed investigative approach yet lack statistical significance due to small samples.

Childhood conditions that feature developmental regression are poorly understood. Phenotype–genotype characterization and diagnostic yield data are needed to inform clinical decision‐making. The aim of this study was to report the conditions featuring developmental regression and assess diagnostic yields of investigations. A retrospective chart review of children presenting with developmental regression to a tertiary pediatric genetic clinic between 2018 and 2021 was performed. Of 99 children, 30% ( n = 30) had intellectual disability (ID), 21% ( n = 21) were autistic, 39% ( n = 39) were autistic with ID, and 9% ( n = 9) did not have ID or autism. Thirty‐two percent ( n = 32) of children received a new diagnosis, including eight molecular findings not previously reported to feature developmental regression. Of the children investigated, exome sequencing (ES) provided the highest diagnostic yield (51.1%, n = 24/47), highest (63.6%, n = 14/22) for children with ID, 50% for autistic children with ID ( n = 6/12) and children without autism or ID ( n = 3/6), and 14.3% ( n = 1/7) for autistic children without ID. We highlight the conditions that feature developmental regression and report on novel phenotypic expansions. The high diagnostic yield of ES, regardless of autism or ID diagnosis, indicates the presence of developmental regression as an opportunity to identify the cause, including for genetic differences not previously reported to include regression.