## 5 Discussion
Collectively, these findings strongly suggest that CELSR1 haploinsufficiency plays a causal role in the development of lymphedema [62]. Orofacial dysmorphic features associated with larger deletions, including enamel defects, supernumerary teeth, thick eyebrows, and the presence of diastema, are well-recognized characteristics of PMS [58; 63]. Furthermore, as highlighted by [PERSON] et al., larger deletions are associated with more severe clinical manifestations [64]. The study by [PERSON] et al. further underscores the considerable heterogeneity in dysmorphic traits among affected individuals, making it challenging to define a consistent phenotypic pattern [18]. The authors describe 32 dysmorphic features, including numerous orofacial abnormalities, such as a bulbous nose, long eyelashes, ear anomalies, full lips, macrocephaly, dolichocephaly, prominent cheekbones, periorbital fullness, a pointed chin, a broad nasal bridge, a long philtrum, malocclusion or widely spaced teeth, micrognathia, deep-set eyes, ptosis, and low-set ears [18]. These findings align with our study, where the significant variability in craniofacial manifestations complicates the identification of consistent facial features in PMS. An observational study by [PERSON] et al. further supports this, indicating that facial features in PMS are neither pathognonomic nor specific, as patients exhibit substantial phenotypic variability, even among those with similar deletion sizes [30]. According to these authors, the only consistent clinical hallmarks of PMS are severe global developmental delay--particularly evident in profound speech impairment--and muscular hypotonia [18]. Nevertheless, certain facial characteristics, including a bulbous nose, pointed chin, ear anomalies, thick eyebrows, long eyelashes, and a broad nasal bridge, have been observed in 35-80% of cases [30]. These traits, along with the features outlined in Table 1, should, therefore, be considered core phenotypic markers of PMS [65; 66; 67]. Several authors have reported craniofacial dysmorphisms in patients carrying mutations in the genes TCF20, ALG12, NAGA, CELSR1, and SCUBE1, which are also involved in early craniofacial development in rodents (Table 3) [31; 68]. Mutations in CELSR1 contributed to both the development of primary lymphedema and neural tube defects, resulting in cranio-cereb abnormalities [31; 69]. Therefore, in the reported case, CELSR1 may have represented a potential geno-phenotypic link between lymphedema and certain craniofacial abnormalities. \begin{table}
\begin{tabular}{p{113.8 pt} p{113.8 pt} p{113.8 pt}} \hline \hline
**Gene** & **Function** & **Clinical Phenotypes** & **Associated Syndromes/Conditions** \\ \hline  & & Severe neurodevelopmental phenotypes, cognitive and motor impairment, autistic features, and ADHD & \\ TCF20 & Coactivator of several transcription factors & Craniofacial dysmorphisms, macroccephaly, scoliosis, seizures, excessive body growth, muscle hypotonia, strabismus, myopia, keratoconus, and constipation. & Smith–Magenis syndrome-like phenotype Potocki–Lupski syndrome \\  & & Recurrent infections & \\  & & Neurodevelopmental delay Muscle hypotonia, progressive microcephaly, failure to thrive, brain MRI alterations & Congenital disorder of glycosylation, type Ig (ALG12-CDG) \\ ALG12 & Encodes for \(\alpha\)6-mannosyltransferase & Reduced coagulation factors, and cardiac defects Crani and skeletal abnormalities, strabismus, retinitis pigmentosa & \\ \hline \hline \end{tabular}
\end{table} 
Table 3: Genetic characteristics of craniofacial dysmorphisms in PMS.