Phelan-McDermid syndrome is caused by pathogenic alterations in SHANK3, located on chromosome 22. The ClinGen classification for this gene-disease relationship is DEFINITIVE. Most cases result from a heterozygous deletion at chromosome 22q13.3 involving at least part of SHANK3, ranging from 50 kilobases to 9 megabases in size; copy number losses and deletions are the principal variant types documented in ClinVar records for this condition. Less commonly, a heterozygous pathogenic variant in SHANK3 or a chromosomal rearrangement disrupting SHANK3 underlies the diagnosis. Some features are attributable to SHANK3 haploinsufficiency alone, while others occur predominantly in individuals with larger deletions that remove adjacent genes.

The condition follows an autosomal dominant inheritance pattern; the large majority of cases arise as de novo alterations not inherited from either parent, and familial transmission is rare. Evidence indicates that small deletions involving SHANK3 may be associated with reduced penetrance — meaning that not all individuals carrying such a deletion will manifest clinical features — and pathogenic variants in SHANK3 have been observed in individuals with apparently non-syndromic autism or schizophrenia. Among individuals who are affected, symptoms can vary considerably in type and severity, a pattern reflecting variable expressivity that is distinct from penetrance.

No established clinical diagnostic criteria exist for Phelan-McDermid syndrome. Diagnosis rests on molecular genetic testing confirming a pathogenic alteration involving SHANK3. Clinical features that prompt diagnostic consideration include moderate-to-profound developmental delay with absent to severely delayed speech, in conjunction with generalized hypotonia, decreased perspiration, autism-like behavioral features, and minor dysmorphic findings including dysplastic toenails and relatively large, fleshy hands.

Chromosomal microarray analysis (CMA) is the initial testing approach most commonly used, as most cases involve large copy number variants not detectable by SHANK3 sequence analysis alone. When CMA identifies a terminal 22q13.3 deletion, karyotype analysis to assess for ring chromosome 22 is an additional step, as individuals with a ring chromosome 22 carry a specific risk for NF2-related schwannomatosis. Gene-targeted deletion/duplication analysis and sequence analysis of SHANK3 are alternatives when gene-specific testing is used; intellectual disability multigene panels that include SHANK3, or comprehensive genomic testing approaches including exome or genome sequencing, may be employed in appropriate clinical contexts.

No treatments are specifically approved by the FDA for Phelan-McDermid syndrome, and no cure exists. Supportive, multidisciplinary care directed at improving quality of life and maximizing function constitutes the management approach for this condition.

For epilepsy, standard anti-seizure medications used in general epilepsy care are employed; none have been demonstrated to be specifically effective for this condition. Sleep disturbances are addressed through behavioral strategies, sleep hygiene measures, and evaluation of contributing conditions. Early intervention and special education services are established components of the developmental management framework. Feeding difficulties may require feeding therapy; gastrostomy tube placement is used in individuals with persistent dysphagia or aspiration risk. Ophthalmologic findings, hearing loss, dental concerns, lymphedema, renal anomalies, and cardiac findings each receive care from specialists in relevant fields as clinically appropriate.

Investigational approaches documented in the published literature include pharmacologic strategies studied for specific behavioral and neurological features, as well as gene therapy approaches targeting SHANK3; these are not approved treatments and remain under active investigation. Because reduced perspiration and a tendency to overheat are documented features in this population, high-temperature and extended sun exposure represent circumstances associated with increased risk. Decreased pain perception in affected individuals warrants ongoing awareness of injury risks from heat, cold, sharp objects, or constrictive clothing and footwear.

Patient assistance programs may be available to help cover treatment costs.

The clinical course of Phelan-McDermid syndrome is variable and correlates in part with deletion size; however, individuals with similar deletion sizes may differ substantially in the degree of disability experienced. Motor milestones are delayed on average: rolling over is achieved at approximately eight months, crawling at approximately 16 months, and independent walking at approximately three years; gait is typically broad-based and unsteady. Speech development in most individuals follows a trajectory of limited early vocabulary acquisition, with many children losing expressive language by approximately age four years. Regression or loss of previously acquired skills occurs in approximately 47% of individuals. Sleep disturbances affecting daily functioning are reported in up to 90% of individuals across the lifespan.

Phelan-McDermid syndrome is an active area of scientific investigation. Several active clinical trials are currently underway, including Phase 1 and Phase 3 studies examining gene therapy approaches and pharmacologic interventions. The published research landscape encompasses numerous studies spanning basic science and preclinical work, with additional literature addressing biomarker research, gene therapy approaches, and recent clinical trial outcomes. Active clinical trials for this condition are listed on ClinicalTrials.gov.