OVERGROWTH SYNDROMES

CDKN1C, DIS3L2, DNMT3A, EED, EZH2, GPC3, HERC1, HIST1H1E, NFIX, NSD1, OFD1

Description

Scientific Background

Overgrowth syndromes are a heterogeneous group of diseases with above average (lengthwise) growth in childhood in common. There is currently no formal definition of overgrowth. It can be generalized (concerning the whole body) or segmental (concerning a part of the body). A suggested definition would be: dysmorphic features plus size and head circumference greater than +2 SD (standard deviations), target size (calculated based on the mean size of the parents) greater than +2 SD.

 

The pediatric large growth syndromes include Beckwith-Wiedeman, Sotos, Weaver, Simpson-Golabi-Behmel, Perlman and Tatton-Brown-Rahman syndromes. The main characteristics are increased pre- and postnatal linear growth, facial abnormalities and partial psychomotor retardation. There are phenotypic overlaps in some syndromes that make clinical differentiation difficult, but there are also characteristic symptoms that suggest a certain suspected diagnosis, such as the combination of large stature, omphalocele and macroglossia in Beckwith-Wiedemann syndrome.

 

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 of the DNMT3A gene, which is one of the genes that code for DNA methyltransferase enzymes. Beckwith-Wiedemann syndrome, which is caused by pathogenic variants in CDKN1C, as well as more frequently by epigenetic alterations on the short arm of chromosome 11, is a special case. In some syndromes there is an increased risk of embryonic tumors, for example a Wilms tumor in Beckwith-Wiedemann and Perlman syndromes for which specific screening measures are recommended.

 

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

GENES

CDKN1C, DIS3L2, DNMT3A, EED, EZH2, GPC3, HERC1, HIST1H1E, NFIX, NSD1, OFD1
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