## 5 Discussion  
PMS is a rare, heterogeneous, and complex neurological developmental disorder, with a phenotype that can vary widely and often manifests clinically without typical features [14; 41; 51]. The management of these patients requires an interdisciplinary approach, involving neonatologists, pediatricians, neurologists, psychiatrists, endocrinologists, immunologists, cardiologists, gastroenterologists, nephrologists, and oral pathologists [41]. Supervision should be led by a geneticist or neuropsychiatric, responsible for coordinating clinical follow-up and providing genetic counseling to families. A comprehensive understanding of developmental characteristics in children is essential for effectively supporting families, identifying specific challenges, and formulating personalized care plans [41]. This study presents the first documented case of hemifacial lymphedema associated with PMS. Clinically, hemifacial lymphedema closely mimics phlegmonous swelling of odontogenic origin [52; 53]. Therefore, a comprehensive intraoral and radiological examination, alongside a detailed assessment of the symptomatology, should be performed by the clinician before proceeding with further diagnostic investigations [52; 54]. Differential diagnosis is crucial to exclude odontogenic inflammatory processes, as misdiagnosis could lead to significant delays in recognizing PMS [52; 53; 54]. Angioneurotic edema should be included in the differential diagnosis, as it presents with rapid, localized swelling of subcutaneous or submucosal tissues, often triggered by allergens, hereditary factors, medications, or physical stimuli, such as cold exposure. Differentiating it from hemifacial lymphedema is essential, as timely recognition and treatment are necessary to prevent complications. Diagnosis relies on a comprehensive medical history, the absence of identifiable triggers or episodic patterns, and targeted laboratory investigations when appropriate [55; 56]. The association between lymphedema and PMS was first described by [PERSON] et al. in 1994 [57]. In PMS, lymphedema may manifest at birth or in early childhood and can progressively worsen if left untreated, leading to significant clinical complications [35]. Lymphedema arises from a dysfunctional lymphatic system, which may result from anatomical or functional abnormalities or an increased lymphatic load, ultimately leading to fluid accumulation [35]. In PMS, lymphedema is classified as primary and is likely attributable to an inadequate lymphatic system. However, the precise mechanisms underlying this lymphatic insufficiency remain unknown, and an as-yet-unidentified gene is suspected to play a causal role [2]. [PERSON] et al. reported a higher prevalence of lymphedema, along with kidney abnormalities, congenital heart defects, abnormal brain imaging, hypotonia, feeding difficulties, and distinct dysmorphic features, in individuals with larger class II deletions [58]. Evidence suggests that alterations in CELSR1 and, to a lesser extent, SHANK3 may contribute to lymphedema pathogenesis [14; 35]. [PERSON] et al. found that CELSR1 haploinsufficiency increased the risk of lymphedema 12-fold [59]. However, while lymphedema has been observed in individuals with SHANK3 variants, its correlation with SHANK3 mutations appears weak, leading researchers to consider these cases incidental [59]. Further studies consistently demonstrated that lymphedema was present in 10.6-23.3% of individuals with 22q13 deletions but absent in those with isolated SHANK3 variants, reinforcing CELSR1 as the more likely candidate gene [30; 36]. [PERSON] et al., in a study on 22q13.31 interstitial deletions, identified CELSR1 as a gene of interest. In a case report of a 20-year-old woman with PMS due to a large deletion and concurrent lymphedema, the authors attributed the condition to the loss of CELSR1 [44; 60]. Beyond PMS, the role of CELSR1 in lymphedema pathogenesis is further supported by findings that loss-of-function variants in CELSR1 are linked to primary and hereditary forms of lymphedema [40; 61].