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To delineate the clinical, neuroimaging, and molecular spectrum of PPP1R21-NDD and outline diagnostic and research priorities. Targeted searches of PubMed, EMBASE, Scopus, Web of Science, and Google Scholar through January 2026 were performed. Eligible reports included molecularly confirmed biallelic PPP1R21 cases and related functional studies. Two researchers independently extracted individual-level data following narrative review quality criteria. Twenty-five individuals from 21 families harbored 17 distinct variants (15 loss-of-function, 2 missense), all homozygous, reflecting high consanguinity. Profound global developmental delay\/intellectual disability was universal; hypotonia near-universal (22\/25, 88%). Ambulation was delayed and ataxic when achieved; expressive language was minimal or absent. A recognizable coarse facial gestalt was observed with thick eyebrows, broad nasal bridge, thick lips, and low-set ears. Systemic features included feeding dysfunction and respiratory morbidity requiring gastrostomy or tracheostomy in severe cases. Mortality was 17% (4\/24). Neuroimaging showed callosal thinning, white-matter volume loss, ventricular enlargement, and vermian hypoplasia. Patient fibroblasts showed delayed transferrin clearance and elevated proteasome activity, suggesting endosomal dysfunction and proteasome hyperactivation. PPP1R21-NDD is a severe recessive encephalopathy with a convergent phenotype and evidence of endo-lysosomal dysfunction. Diagnosis should be pursued with exome or genome sequencing in patients with characteristic clinical and neuroimaging features, particularly in consanguineous families. Research priorities include natural history studies, standardized magnetic resonance imaging (MRI) protocols, neural disease models, and therapeutic strategies targeting endosomal trafficking.\n                  <\/jats:p>","DOI":"10.1007\/s10048-026-00920-4","type":"journal-article","created":{"date-parts":[[2026,8,8]],"date-time":"2026-08-08T08:07:14Z","timestamp":1786176434000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["PPP1R21-Related neurodevelopmental disorder: Phenotypic delineation, variant spectrum, and pathophysiological mechanisms"],"prefix":"10.1007","volume":"27","author":[{"given":"Francesco Fabrizio","family":"Comisi","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gabriele","family":"Di Pasquale","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-5479-4333","authenticated-orcid":false,"given":"Andrea Maria","family":"Comisi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giuseppe Donato","family":"Mangano","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Piero","family":"Pavone","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessandro","family":"Ferretti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vincenzo","family":"Salpietro","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pasquale","family":"Parisi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alberto","family":"Spalice","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,8,8]]},"reference":[{"key":"920_CR1","doi-asserted-by":"publisher","first-page":"267","DOI":"10.1002\/humu.23694","volume":"40","author":"AU Rehman","year":"2019","unstructured":"Rehman AU, Najafi M, Kambouris M, Al-Gazali L, Makrythanasis P, Rad A, Maroofian R, Rajab A, Stark Z, Hunter JV et al (2019) Biallelic Loss of Function Variants in PPP1R21 Cause a Neurodevelopmental Syndrome with Impaired Endocytic Function. 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Published case reports and small series describe global developmental delay, epilepsy, coarse facial features, and white-matter abnormalities, but no systematic phenotypic synthesis exists. Functional studies in patient fibroblasts suggest disrupted endo-lysosomal trafficking and altered proteasome activity","order":4,"name":"Ethics","label":"What is already known about this topic","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"First comprehensive review of all 25 molecularly confirmed individuals, with phenotypic frequencies, standardized denominators, and individual-level data in Online Resources\n                      \n                      ,\n                      \n                      , and\n                      \n                      . Description of a recurrent neuroimaging pattern combining supratentorial white-matter volume loss, thin corpus callosum, and cerebellar atrophy. A proposed pathophysiological model linking endosomal mRNA transport, proteostasis, and mTOR signaling, with a structured research agenda for preclinical validation","order":5,"name":"Ethics","label":"What this study adds","group":{"name":"EthicsHeading","label":"Declarations"}}],"article-number":"54"}}