Lateralized and Segmental Overgrowth in Children

Abstract

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.

Keywords: Beckwith–Wiedemann; PIK3CA; PROS; cancer predisposition; cancer screening; lateralized; mosaic; overgrowth; segmental; somatic.

Figure 1

The Spectrum of the Beckwith–Wiedemann Syndrome (BWSp) includes (1) patients with “typical Beckwith–Wiedemann syndrome (BWS) with a clinical diagnosis (score ≥ 4 points) with or without an (epi)genetic change at 11p15.5 imprinted region, (2) patients with “atypical forms” (defined as those with a score < 4 points) plus an (epi)genetic change at the BWS locus, and (3) patients with isolated lateralized overgrowth (ILO) plus an (epi)genetic change at the 11p15.5 locus.

Figure 2

Molecular defects in Beckwith–Wiedemann spectrum (BWSp). (a) Normal functioning of the paternal (blue) and maternal (red) 11p15 imprinted domains. The centromeric domain is regulated by the imprinting center 2 (IC2) which methylation regulates the expression of KCNQ1, KCNQ1OT1 (KCNQ1 Opposite Strand/Antisense Transcript 1), and CDKN1C expression. Normally, KCNQ1 and CDKN1C are expressed by the maternal alleles and silenced on the paternal ones, while KCNQ1OT1 is expressed only by the paternal one. The telomeric domain is regulated by the IC1: methylation on the paternal chromosome silences H19 and allows IGF2 expression. BWSp can be caused by: (b) IC2 loss of methylation (IC2-LoM) on maternal chromosome leading to reduced expression CDKN1C; (c) gain of methylation at maternal IC1 (IC1-GoM) leading to biallelic IGF2 and reduced H19 expression; (d) chromosome 11 paternal uniparental disomy (UPD(11)pat), leading to both expression anomalies seen in IC2-LoM and IC1-GoM; (e) CDKN1C loss-of-function mutations on the maternal chromosome. The latter are dominant and lead to BWSp phenotype only when inherited from the mother.

Figure 3

Lateralized Overgrowth (LO) in patients within the Beckwith–Wiedemann spectrum (BWSp). Isolated LO with Imprinting Center 2 Loss of Methylation (IC2-LoM, (A)), paternal uniparental disomy of chromosome 11 (UPD(11)pat) (B,H,I), and IC1 Gain of Methylation (IC1-GoM, (D,E)); severe LO in patients with BWSp clinical criteria and UPD(11)pat (C,F,G).

Figure 4

Lateralized Overgrowth (LO) in patients within the PIK3CA-related Overgrowth Spectrum (PROS). The latter include cases with megalencephaly-capillary malformation syndrome (MCAP, (A,B)), fibroadipose overgrowth with vascular anomalies (FAVA, (C,D,J–L)), Klippel-Trenaunay syndrome (KTS, (E–H)), congenital lipomatous overgrowth, vascular malformations, epidermal nevi, scoliosis/skeletal and spinal syndrome (CLOVES, (I)), hemihyperplasia multiple lipomatosis (HHML, (M)).