Updated Consensus Guidelines on the Management of Phelan-McDermid Syndrome

Phelan-McDermid syndrome (PMS) is a genetic condition caused by SHANK3 haploinsufficiency and characterized by a wide range of neurodevelopmental and systemic manifestations. The first practice parameters for assessment and monitoring in individuals with PMS were published in 2014; recently, knowledge about PMS has grown significantly based on data from longitudinal phenotyping studies and large-scale genotype-phenotype investigations. The objective of these updated clinical management guidelines was to: (1) reflect the latest in knowledge in PMS and (2) provide guidance for clinicians, researchers, and the general community. A taskforce was established with clinical experts in PMS and representatives from the parent community. Experts joined subgroups based on their areas of specialty, including genetics, neurology, neurodevelopment, gastroenterology, primary care, physiatry, nephrology, endocrinology, cardiology, gynecology, and dentistry. Taskforce members convened regularly between 2021 and 2022 and produced specialty-specific guidelines based on iterative feedback and discussion. Taskforce leaders then established consensus within their respective specialty group and harmonized the guidelines. The knowledge gained over the past decade allows for improved guidelines to assess and monitor individuals with PMS. Since there is limited evidence specific to PMS, intervention mostly follows general guidelines for treating individuals with developmental disorders. Significant evidence has been amassed to guide the management of comorbid neuropsychiatric conditions in PMS, albeit mainly from caregiver report and the experience of clinical experts. These updated consensus guidelines on the management of PMS represent an advance for the field and will improve care in the community. Several areas for future research are also highlighted and will contribute to subsequent updates with more refined and specific recommendations as new knowledge accumulates.

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References

Hussong J, Wagner C, Curfs L, von Gontard A . Incontinence and psychological symptoms in Phelan-McDermid syndrome. Neurourol Urodyn. 2019; 39(1):310-318. DOI: 10.1002/nau.24197. View

Mieses A, Tavassoli T, Li E, Soorya L, Lurie S, Wang A . Brief Report: Sensory Reactivity in Children with Phelan-McDermid Syndrome. J Autism Dev Disord. 2016; 46(7):2508-13. DOI: 10.1007/s10803-016-2754-0. View

Fu J, Satterstrom F, Peng M, Brand H, Collins R, Dong S . Rare coding variation provides insight into the genetic architecture and phenotypic context of autism. Nat Genet. 2022; 54(9):1320-1331. PMC: 9653013. DOI: 10.1038/s41588-022-01104-0. View

Lasota J, Wasag B, Dansonka-Mieszkowska A, Karcz D, Millward C, Rys J . Evaluation of NF2 and NF1 tumor suppressor genes in distinctive gastrointestinal nerve sheath tumors traditionally diagnosed as benign schwannomas: s study of 20 cases. Lab Invest. 2003; 83(9):1361-71. DOI: 10.1097/01.lab.0000087591.29639.e3. View

De Rubeis S, Siper P, Durkin A, Weissman J, Muratet F, Halpern D . Delineation of the genetic and clinical spectrum of Phelan-McDermid syndrome caused by point mutations. Mol Autism. 2018; 9:31. PMC: 5921983. DOI: 10.1186/s13229-018-0205-9. View

Srikanth S, Jain L, Zepeda-Mendoza C, Cascio L, Jones K, Pauly R . Position effects of 22q13 rearrangements on candidate genes in Phelan-McDermid syndrome. PLoS One. 2021; 16(7):e0253859. PMC: 8259982. DOI: 10.1371/journal.pone.0253859. View

Rollins J, Sarasua S, Phelan K, DuPont B, Rogers R, Collins J . Growth in Phelan-McDermid syndrome. Am J Med Genet A. 2011; 155A(9):2324-6. DOI: 10.1002/ajmg.a.34158. View

Kresbach C, Dorostkar M, Suwala A, Wefers A, Schweizer L, Engertsberger L . Neurofibromatosis type 2 predisposes to ependymomas of various localization, histology, and molecular subtype. Acta Neuropathol. 2021; 141(6):971-974. PMC: 8113165. DOI: 10.1007/s00401-021-02304-4. View

Norwood Jr K, Slayton R . Oral health care for children with developmental disabilities. Pediatrics. 2013; 131(3):614-9. DOI: 10.1542/peds.2012-3650. View

10.

Maltese P, Michelini S, Ricci M, Maitz S, Fiorentino A, Serrani R . Increasing evidence of hereditary lymphedema caused by CELSR1 loss-of-function variants. Am J Med Genet A. 2019; 179(9):1718-1724. DOI: 10.1002/ajmg.a.61269. View

11.

Moffitt B, Sarasua S, Ward L, Ivankovic D, Valentine K, Rogers C . Sleep and Phelan-McDermid Syndrome: Lessons from the International Registry and the scientific literature. Mol Genet Genomic Med. 2022; 10(10):e2035. PMC: 9544216. DOI: 10.1002/mgg3.2035. View

12.

von Gontard A . Urinary incontinence in children with special needs. Nat Rev Urol. 2013; 10(11):667-74. DOI: 10.1038/nrurol.2013.213. View

13.

Eldevik S, Hastings R, Hughes J, Jahr E, Eikeseth S, Cross S . Meta-analysis of Early Intensive Behavioral Intervention for children with autism. J Clin Child Adolesc Psychol. 2009; 38(3):439-50. DOI: 10.1080/15374410902851739. View

14.

Bonaglia M, Giorda R, Borgatti R, Felisari G, Gagliardi C, Selicorni A . Disruption of the ProSAP2 gene in a t(12;22)(q24.1;q13.3) is associated with the 22q13.3 deletion syndrome. Am J Hum Genet. 2001; 69(2):261-8. PMC: 1235301. DOI: 10.1086/321293. View

15.

Leblond C, Nava C, Polge A, Gauthier J, Huguet G, Lumbroso S . Meta-analysis of SHANK Mutations in Autism Spectrum Disorders: a gradient of severity in cognitive impairments. PLoS Genet. 2014; 10(9):e1004580. PMC: 4154644. DOI: 10.1371/journal.pgen.1004580. View

16.

Egger J, Zwanenburg R, van Ravenswaaij-Arts C, Kleefstra T, Verhoeven W . Neuropsychological phenotype and psychopathology in seven adult patients with Phelan-McDermid syndrome: implications for treatment strategy. Genes Brain Behav. 2016; 15(4):395-404. DOI: 10.1111/gbb.12285. View

17.

Kolevzon A, Breen M, Siper P, Halpern D, Frank Y, Rieger H . Clinical trial of insulin-like growth factor-1 in Phelan-McDermid syndrome. Mol Autism. 2022; 13(1):17. PMC: 8994375. DOI: 10.1186/s13229-022-00493-7. View

18.

Greenwood N, Wilkinson J . Sexual and reproductive health care for women with intellectual disabilities: a primary care perspective. Int J Family Med. 2014; 2013:642472. PMC: 3876698. DOI: 10.1155/2013/642472. View

19.

Erickson R, Lai L, Mustacich D, Bernas M, Kuo P, Witte M . Sex-limited penetrance of lymphedema to females with CELSR1 haploinsufficiency: A second family. Clin Genet. 2019; 96(5):478-482. DOI: 10.1111/cge.13622. View

20.

Nesslinger N, Gorski J, Kurczynski T, Shapira S, Siegel-Bartelt J, Dumanski J . Clinical, cytogenetic, and molecular characterization of seven patients with deletions of chromosome 22q13.3. Am J Hum Genet. 1994; 54(3):464-72. PMC: 1918126. View