SCIENTIFIC BACKGROUND

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

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

 

 

SOTOS AND WEAVER SYNDROME

Sotos syndrome is an overgrowth syndrome of childhood that is characterized by macrocephaly, distinctive craniofacial features, mild intellectual disability (IQ average 76), advanced bone age, and normal height in adulthood. The head is narrow and long (dolichocephalic), the forehead high and broad with a laterally receding frontal hairline, and the is chin accentuated and pointed. The distance between the eyes seems widened, and the eyelids slope downwards. The palate is pointed and high. Hands and feet are large and the joints are often hyperextensible. Feeding problems are common in infancy. About 50% of the children have seizures, and about half of them occur with fever. Congenital malformations such as heart defects are rare. A slightly increased tumor rate has been reported involving various tissues. Increased anxiety, hyperactivity and aggressiveness are often described.

 

In 75-90% of cases, Sotos syndrome is caused by nucleotide alterations or deletions in the NSD1 gene (nuclear receptor-binding SET domain-containing protein 1) in 5q35. In Central Europe and the USA, 60-80% of patients carry nucleotide changes and about 10% carry deletions, while in Japanese patients, microdeletions are causal in over 50%. The frequency of Sotos syndrome is estimated at 1:10,000 to 1:50,000. The recurrence risk for siblings is low because the nucleotide changes or deletions are mostly new.

 

Weaver syndrome (WVS; OMIM 277590), a rare autosomal dominant disorder characterized by tall stature, variable intellectual disability and characteristic facial dysmorphia, offers a potential differential diagnosis. Pathogenic variants in the EZH2 gene (enhancer of zeste, Drosophila, homolog 2; OMIM 601573) have been found to be causative for a large number of Weaver syndrome cases. However, genetic heterogeneity cannot be excluded.

 

References

Lane & Freeth 2019, Chromatin Signaling and Neurological Disorders, Vol 7, pp. 219 / Tatton-Brown et al., Sotos Syndrome. 2004 Dec 17 [Updated 2019 Aug 1]. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2021 / Imagawa et al. 2017, Hum Mutat 38:637 / Leventopoulos et al. 2009, Pediatr Neurol 40:357 / Tatton-Brown et al. 2007, Eur J Hum Genet 15:264 / Baujat et al. 2007, Orphanet J Rare Dis 2:36 / Visser et al. 2005, Am J Hum Genet 76:52 / Rio et al. 2003, J Med Genet 40:436 / Kurotaki et al. 2002, Nat Genet 30:365

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