Lateralized and Segmental Overgrowth in Children

Congenital disorders of lateralized or segmental overgrowth (LO) are heterogeneous conditions with increased tissue growth in a body region. 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. 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 is caused by either genetic or epigenetic somatic anomalies affecting cell proliferation. Most LOs are classifiable in the Beckwith–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). These disorders overlap over common phenotypes, making their appraisal and distinction challenging. The latter is crucial, as specific management strategies are key: some LO is associated with increased cancer risk making imperative tumor screening since childhood. 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.

Reductive Otoplasty and Facial Debulking in a Pediatric Patient With PIK3CA-Related Overgrowth

Overgrowth syndromes encompass a number of rare genetic diseases with heterogeneous clinical phenotypes. Accordingly, there is a strong imperative to collect data and classify these disorders to aid in diagnosis and management. Recent advances in the genetics of overgrowth syndromes have identified mutations in the PIK3CA gene. These somatic mutations manifest in progressive segmental overgrowth of fibrous and adipose tissue and bone, vascular malformations, and in some cases, increased risk for malignancy. Targeted medical therapy is under investigation for the management of PROS, but treatment of overgrowth relies on surgical debulking. Macrotia in PIK3CA-related overgrowth spectrum (PROS) has not been reported in the literature. In this case, we discuss a novel approach to reductive otoplasty and facial soft tissue debulking in a pediatric patient with PROS.

Low-level variant calling for non-matched samples using a position-based and nucleotide-specific approach

Background The widespread use of next-generation sequencing has identified an important role for somatic mosaicism in many diseases. However, detecting low-level mosaic variants from next-generation sequencing data remains challenging. Results Here, we present a method for Position-Based Variant Identification (PBVI) that uses empirically-derived distributions of alternate nucleotides from a control dataset. We modeled this approach on 11 segmental overgrowth genes. We show that this method improves detection of single nucleotide mosaic variants of 0.01–0.05 variant allele fraction compared to other low-level variant callers. At depths of 600 × and 1200 ×, we observed > 85% and > 95% sensitivity, respectively. In a cohort of 26 individuals with somatic overgrowth disorders PBVI showed improved signal to noise, identifying pathogenic variants in 17 individuals. Conclusion PBVI can facilitate identification of low-level mosaic variants thus increasing the utility of next-generation sequencing data for research and diagnostic purposes.

Lymphangioma of the fetal neck within the PIK3CA-Related-Overgrowth Spectrum (PROS): A case report.

Neck tumors are rare fetal conditions. They can receive their growth stimuli by activating missense mutations characterizing disorders with benign overgrowth, collectively known as PIK3CA-Related-Overgrowth-Spectrum. This results in segmental overgrowth with phenotypic variation, genetic heterogeneity or tissue specific distribution. Thus, clinical and molecular diagnosis as well as treatment remains challenging.

Characterization and Childhood Tumor Risk Assessment of Genetic and Epigenetic Syndromes Associated With Lateralized Overgrowth

Lateralized overgrowth (LO), or segmental overgrowth, is defined as an increase in growth of tissue (bone, muscle, connective tissue, vasculature, etc.) in any region of the body. Some overgrowth syndromes, characterized by both generalized and lateralized overgrowth, have been associated with an increased risk of tumor development. This may be due to the underlying genetic and epigenetic defects that lead to disrupted cell growth and proliferation pathways resulting in the overgrowth and tumor phenotypes. This chapter focuses on the four most common syndromes characterized by LO: Beckwith-Wiedemann spectrum (BWSp), PIK3CA-related overgrowth spectrum (PROS), Proteus syndrome (PS), and PTEN hamartoma tumor syndrome (PHTS). These syndromes demonstrate variable risks for tumor development in patients affected by LO, and we provide a comprehensive literature review of all common tumors reported in patients diagnosed with an LO-related disorder. This review summarizes the current data on tumor risk among these disorders and their associated tumor screening guidelines. Furthermore, this chapter highlights the importance of an accurate diagnosis when a patient presents with LO as similar phenotypes are associated with different tumor risks, thereby altering preventative screening protocols.

PIK3CA-Related Overgrowth Spectrum

Postzygotic mutations of the PIK3CA gene are associated with a series of clinical phenotypes characterized by segmental overgrowth and recently grouped under the term PIK3CA-related overgrowth spectrum (PROS). This chapter provides an overview of the clinical features shared by the phenotypes in PROS, including both the conditions with isolated features and the ones with syndromal presentation. The somatic overgrowth in cases with PROS is asymmetric, progressive, and “ballooning” in appearance and tends to involve predominantly the limbs, including fingers and toes, although the trunk and face are often affected as well. The tissues affected in the overgrowth can include all or some of these types: fibrous, adipose, vascular, nervous, and skeletal. Somatic gain-of-function mutations of PIK3CA cause activation of the PI3K-AKT pathway, leading to excessive cell growth and proliferation. Timing of PIK3CA mutations, tissue specificity, and type of mutation may play a role in the phenotypic variability of PROS.

Proteus Syndrome

Proteus syndrome is an exceedingly rare disorder, perhaps the least common of all overgrowth syndromes but one of the most distinctive because of its segmental nature and unrelenting progression. Proteus syndrome occurs sporadically and was the first of the segmental overgrowth syndromes found to be caused by somatic mosaicism. The discovery of an activating mutation in AKT1 by Les Biesecker and colleagues at the National Institutes of Health provided the initial molecular proof for somatic mosaicism in Proteus syndrome. Overgrowth in Proteus syndrome can involve nearly any tissue or part of the body. Presumably a germline mutation that would affect all tissues of the body would be lethal. Overgrowth of a tissue or a body part is the distinctive manifestation of Proteus syndrome but in most cases will be accompanied by other cutaneous, skeletal, vascular, or soft tissue findings. Although the possibility of an increased risk for developing neoplastic disease is a concern in any overgrowth disorder, this has not been demonstrated in Proteus syndrome.