Updated consensus guidelines on the management of Phelan-McDermid syndrome

Abstract

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.

Keywords: Phelan-McDermid syndrome; SHANK3; assessment; autism spectrum disorder; monitoring; treatment.

Figure 1:

Recommendations for parental testing in Phelan-McDermid syndrome (PMS). We recommend parental testing following the identification of a 22q13 deletion including SHANK3 or a pathogenic SHANK3 sequence variant (orange). The estimated risk of familial recurrence (light blue) depends on the nature of the pathogenic variant (purple) in the proband and the results of parental testing (green). Karyotype and FISH can be used for parental evaluation of most deletions (see note below). Targeted sequencing may be used for parental evaluation of pathogenic SHANK3 variants. FISH=fluorescence in situ hybridization. **When a deletion in a patient is smaller than can be detected by FISH, CMA or NGS-based methods can potentially be used for parental testing with the understanding that balanced rearrangements may not be detected.