OVERGROWTH SYNDROMES PANEL

Overview

Overgrowth syndromes refer to a variety of disorders characterized by above-average growth in childhood, with characteristics such as height and head circumference greater than +2 standard deviations. These syndromes include Beckwith-Wiedemann, Sotos, and Weaver syndromes, among others. Characteristic symptoms vary, but many show facial abnormalities and developmental disorders. Some of these syndromes increase the risk of certain tumors.

Symptoms

Overgrowth syndromes are a heterogeneous group of diseases with above average (height) growth in childhood in common. There is currently no formal definition of overgrowth. It can be generalized (affecting the entire body) or segmental (affecting part of the body). A suggested definition would be:

The main characteristics are:

• Increased pre- and postnatal linear growth
• Facial abnormalities
• Global developmental disorders (in some cases)

The pediatric overgrowth syndromes include Beckwith-Wiedeman, Sotos, Weaver, Simpson-Golabi-Behmel, Perlman, and Tatton-Brown-Rahman syndromes.

Some of these syndromes have overlapping phenotypes, which makes clinical differentiation difficult, but they also have characteristic symptoms that point to a certain suspected diagnosis, such as the combination of tall stature, omphalocele, and macroglossia in Beckwith-Wiedemann syndrome.

Some of these syndromes are associated with an increased risk of embryonic tumors, particularly Wilms tumor in Beckwith-Wiedemann and Perlman syndromes, for which specific screening measures are recommended.

Cause

Changes in various genes, such as NSD1 (Sotos syndrome 1), NFIX (Sotos syndrome 2) and EZH2 (Weaver syndrome) form the molecular basis of the syndromes, and the investigation of these can help to clarify the differential diagnosis.

Tatton-Brown-Rahman syndrome, also known as DNMT3A overgrowth syndrome, is caused by pathogenic variants in the DNMT3A gene. This is one of the genes that code for DNA methyltransferase enzymes.

Beckwith-Wiedemann syndrome is a special case, as it is caused not only by pathogenic variants in CDKN1C, but more frequently by epigenetic changes on the short arm of chromosome 11.

References

Kamien et al. 2018 Mol Syndromol 9:70 / Tatton-Brown et al. 2017 Am J Hum Genet 100: 725 / da Silva Lacerda et al. 2014, Radiol Res and Pract, Article ID 947451 / Tatton-Brown et al. 2014, Nat Genet 46:385 / Tatton-Brown et al. 2013, Am J Med Genet C Semin Med Genet 163C:71 / Neylon et al. 2012 Curr Opin Pediatr 24:505