###### Abstract  
Phelan-McDermid syndrome (PMS) is a rare genetic disorder primarily caused by deletions or structural alterations of chromosome 22q13, often involving the SHANK3 gene. However, mutations in other genes, such as CELSR1, or deletions in the interstitial regions of 22q13 contribute to the phenotypic variability of PMS. The syndrome is characterized by developmental delay, cognitive impairment, absent or significant impairment speech, autism spectrum disorder (ASD), and distinctive craniofacial features. Lymphedema, present in 10-25% of cases, typically affects peripheral regions, while facial involvement has not been documented to date. Orofacial manifestations frequently include dolichoccephaly, widely spaced eyes, prominent ears, and dysmorphic features, such as a bulbous nose and arched palate. This scoping review analyzed seven studies on orofacial features associated with PMS, highlighting a higher phenotypic variability, with frequent findings of intellectual disability, hypotonia, and craniofacial dysmorphisms. Genomic analyses identified consistent deletions in 22q13.31-q13.33 and complex genomic rearrangements. This review, through the report of the first documented case of hemifacialymphedema in the literature, analyzes the facial features of patients with PMS and their genetic origins. It also highlights the importance of interdisciplinary collaboration and inclusive genetic testing to better define the phenotypic spectrum of this syndrome. A deeper understanding of the genetic and clinical characteristics of PMS can facilitate early diagnosis and personalized management for these patients. Phelan-McDermid syndrome; lymphedema; orofacial lymphedema  
13 January  
and patient registry of the Phelan-McDermid Syndrome Foundation (PMSF) include over 3216 individuals diagnosed with PMS worldwide ([[https://pmsf.org](https://pmsf.org)]([https://pmsf.org](https://pmsf.org))) [1; 2; 4; 9]. PMS is predominantly attributed to de novo deletions of chromosome 22, frequently of paternal origin, or to unbalanced chromosomal rearrangements inherited from a parent with a balanced translocation [2; 10; 11]. The SHANK3 gene is believed to underpin the syndrome's key neurological features, such as speech delay, intellectual disability, and autistic traits [2; 11; 12; 13; 14; 15; 16]. Genotype-phenotype correlation studies revealed an association between deletion size and specific clinical features, such as developmental delay, dysmorphic traits, medical comorbidities, hypotonia, and communication impairment, with larger deletions generally resulting in more severe phenotypic outcomes [17; 18; 19; 20; 21; 22]. The contribution of genes beyond SHANK3 was emphasized by the identification of PMS-compatible phenotypes in individuals with interstitial 22q13 deletions that preserve SHANK3, thereby distinguishing SHANK3-related and SHANK3-unrelated forms of PMS [17; 23; 24; 25; 26]. Evidence suggests that multiple additional genes contribute to the pathogenesis of PMS [8; 14]. The deletion of multiple interstitial genes, including MMPED1 and CYB5R3 in 22q13.2, as well as FBLN1, NUP50, C22 orf9, KIAA1644, PARVB, TRMU, WNT7B, ATXN10, and microRNAs, such as hsa-mir-1249, hsa-let-7a-3, and hsa-let7 in 22q13.31, may result in consequences comparable to the haploinsufficiency of SHANK3 and other terminal genes [27]. PMS presents with neonatal hypotonia, significantly delayed or absent speech, developmental delay, and mild dysmorphic facial features. The majority of affected individuals present with moderate to profound intellectual disability [7; 24; 25; 28; 29]. Additional clinical features include large fleshy hands, dysplastic toenails, and decreased perspiration, leading to a predisposition to overheating [24]. Unlike other autosomal chromosome disorders, individuals with PMS typically exhibit normal stature and head circumference. Behavioral manifestations often include mouthing or chewing non-food items, reduced pain sensitivity, and the presence of autism spectrum disorder or autistic-like affect and behavior [24; 25].