LO can be part of a syndrome or isolated. LO may be caused by genetic or epigenetic defects leading to disruption in cell growth and over signaling in cellular proliferation pathways resulting in tissue overgrowth and cell proliferation. However, these measurements are not standardized as yet.

Objective methods, such as tape measurements or imaging studies of both soft and skeletal tissue by computed tomography, magnetic resonance, 3D technologies or DEXA scanning can be useful to better define, characterize and quantify the degree of LO and in the differential diagnosis of such overgrowth disorders. Indeed, there is no need for imaging studies to define LO: LOs are subjective and evident at the clinical evaluation (i.e., вЂњfrom the end of the bedвЂќ). This threshold is theoretical and underlines that it is considered physiological to have minor asymmetries in certain areas of the body: an example is represented by the very common clinical finding of discrepancy in the length of the lower limbs of less than one centimeter that occurs in many adults. Asymmetry is generally considered pathological if it exceeds at least 10% compared to the contralateral area. LO often leads to body asymmetry caused by an increase in the length/circumference of a limb, or in body region volume. The latter largely referred to body/hemi hyperplasia/hypertrophy, terms that implicated the histologic definition of cell proliferation or increased cell size, respectively. LO and segmental overgrowth are used synonymously and currently replace the previous nomenclature. Lateralized overgrowth (LO), or segmental overgrowth, is defined as an increase in tissue growth of various origins (skeletal, muscular, fibrous, vascular, adipose, or any association of these) in any region of the body. Interestingly, some LO shares molecular mechanisms with cancer: recent advances in tumor biological pathway druggability and growth downregulation offer new avenues for the treatment of the most severe and complicated LO. The latter is crucial, as specific management strategies are key: some LO is associated with increased cancer risk making imperative tumor screening since childhood. These disorders overlap over common phenotypes, making their appraisal and distinction challenging. Most LOs are classifiable in the BeckwithвЂ“Wiedemann spectrum (BWSp), PI3KCA/AKT-related overgrowth spectrum (PROS/AROS), mosaic RASopathies, PTEN Hamartoma Tumor Syndrome, mosaic activating variants in angiogenesis pathways, and isolated LO (ILO).

LO is caused by either genetic or epigenetic somatic anomalies affecting cell proliferation. Recently, next-generation sequencing approaches have increased the knowledge on the molecular defects in LO, allowing classifying them based on the deranged cellular signaling pathway. LO can affect every region, be localized or extensive, involve one or several embryonic tissues, showing variable severity, from mild forms with minor body asymmetry to severe ones with progressive tissue growth and related relevant complications. Congenital disorders of lateralized or segmental overgrowth (LO) are heterogeneous conditions with increased tissue growth in a body region.

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