Ann Pediatr Endocrinol Metab.  2013 Sep;18(3):101-105. 10.6065/apem.2013.18.3.101.

Genetic syndromes associated with overgrowth in childhood

• Ko JM

• KMID: 2266359
• DOI: http://doi.org/10.6065/apem.2013.18.3.101

Abstract

Overgrowth syndromes comprise a diverse group of conditions with unique clinical, behavioral and molecular genetic features. While considerable overlap in presentation sometimes exists, advances in identification of the precise etiology of specific overgrowth disorders continue to improve clinicians' ability to make an accurate diagnosis. Among them, this paper introduces two classic genetic overgrowth syndromes: Sotos syndrome and Beckwith-Wiedemann syndrome. Historically, the diagnosis was based entirely on clinical findings. However, it is now understood that Sotos syndrome is caused by a variety of molecular genetic alterations resulting in haploinsufficiency of the NSD1 gene at chromosome 5q35 and that Beckwith-Wiedemann syndrome is caused by heterogeneous abnormalities in the imprinting of a number of growth regulatory genes within chromosome 11p15 in the majority of cases. Interestingly, the 11p15 imprinting region is also associated with Russell-Silver syndrome which is a typical growth retardation syndrome. Opposite epigenetic alterations in 11p15 result in opposite clinical features shown in Beckwith-Wiedemann syndrome and Russell-Silver syndrome. Although the exact functions of the causing genes have not yet been completely understood, these overgrowth syndromes can be good models to clarify the complex basis of human growth and help to develop better-directed therapies in the future.

Keyword

Macrosomia; Sotos syndrome; Beckwith-Wiedemann syndrome; genomic imprinting

MeSH Terms

Beckwith-Wiedemann Syndrome*
Epigenomics
Genes, Regulator
Genomic Imprinting
Haploinsufficiency
Humans
Molecular Biology
Silver-Russell Syndrome
Sotos Syndrome*

Figure

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  Fig. 1 Chromosome 5q35 microdeletions are more frequently found in Japanese patients with Sotos syndrome, whereas 5q35 microdeletions are uncommon in patients outside of Japan.

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  Fig. 2 Chromosome 11p15 region has two imprinting domains (domain 1 and 2) and four major genes (IGF2, H19, CDKN1C, and KCNQ10T1) associated with genomic imprinting.

Reference

1. Neylon OM, Werther GA, Sabin MA. Overgrowth syndromes. Curr Opin Pediatr. 2012; 24:505–511. PMID: 22705997.

2. Tatton-Brown K, Rahman N. Sotos syndrome. Eur J Hum Genet. 2007; 15:264–271. PMID: 16969376.

3. Tatton-Brown K, Douglas J, Coleman K, Baujat G, Cole TR, Das S, et al. Genotype-phenotype associations in Sotos syndrome: an analysis of 266 individuals with NSD1 aberrations. Am J Hum Genet. 2005; 77:193–204. PMID: 15942875.

4. Sotos JF, Dodge PR, Muirhead D, Crawford JD, Talbot NB. Cerebral gigantism in childhood: a syndrome of excessively rapid growth and acromegalic features and a nonprogressive neurologic disorder. N Engl J Med. 1964; 271:109–116. PMID: 14148233.

5. Cole TR, Hughes HE. Sotos syndrome: a study of the diagnostic criteria and natural history. J Med Genet. 1994; 31:20–32. PMID: 7512144.

6. Agwu JC, Shaw NJ, Kirk J, Chapman S, Ravine D, Cole TR. Growth in Sotos syndrome. Arch Dis Child. 1999; 80:339–342. PMID: 10086939.

7. Allanson JE, Cole TR. Sotos syndrome: evolution of facial phenotype subjective and objective assessment. Am J Med Genet. 1996; 65:13–20. PMID: 8914735.

8. Wit JM, Beemer FA, Barth PG, Oorthuys JW, Dijkstra PF, Van den Brande JL, et al. Cerebral gigantism (Sotos syndrome). Compiled data of 22 cases. Analysis of clinical features, growth and plasma somatomedin. Eur J Pediatr. 1985; 144:131–140. PMID: 4043122.

9. Hersh JH, Cole TR, Bloom AS, Bertolone SJ, Hughes HE. Risk of malignancy in Sotos syndrome. J Pediatr. 1992; 120(4 Pt 1):572–574. PMID: 1552397.

10. Kurotaki N, Imaizumi K, Harada N, Masuno M, Kondoh T, Nagai T, et al. Haploinsufficiency of NSD1 causes Sotos syndrome. Nat Genet. 2002; 30:365–366. PMID: 11896389.

11. de Boer L, Kant SG, Karperien M, van Beers L, Tjon J, Vink GR, et al. Genotype-phenotype correlation in patients suspected of having Sotos syndrome. Horm Res. 2004; 62:197–207. PMID: 15452385.

12. Kurotaki N, Harada N, Yoshiura K, Sugano S, Niikawa N, Matsumoto N. Molecular characterization of NSD1, a human homologue of the mouse Nsd1 gene. Gene. 2001; 279:197–204. PMID: 11733144.

13. Huang N, vom Baur E, Garnier JM, Lerouge T, Vonesch JL, Lutz Y, et al. Two distinct nuclear receptor interaction domains in NSD1, a novel SET protein that exhibits characteristics of both corepressors and coactivators. EMBO J. 1998; 17:3398–3412. PMID: 9628876.

14. Sohn YB, Lee CG, Ko JM, Yang JA, Yun JN, Jung EJ, et al. Clinical and genetic spectrum of 18 unrelated Korean patients with Sotos syndrome: frequent 5q35 microdeletion and identification of four novel NSD1 mutations. J Hum Genet. 2013; 58:73–77. PMID: 23190751.

15. Niikawa N. Molecular basis of Sotos syndrome. Horm Res. 2004; 62(Suppl 3):60–65. PMID: 15539801.

16. Nagai T, Matsumoto N, Kurotaki N, Harada N, Niikawa N, Ogata T, et al. Sotos syndrome and haploinsufficiency of NSD1: clinical features of intragenic mutations and submicroscopic deletions. J Med Genet. 2003; 40:285–289. PMID: 12676901.

17. Engström W, Lindham S, Schofield P. Wiedemann-Beckwith syndrome. Eur J Pediatr. 1988; 147:450–457. PMID: 3044795.

18. Greer KJ, Kirkpatrick SJ, Weksberg R, Pauli RM. Beckwith-Wiedemann syndrome in adults: observations from one family and recommendations for care. Am J Med Genet A. 2008; 146A:1707–1712. PMID: 18546283.

19. Choufani S, Shuman C, Weksberg R. Beckwith-Wiedemann syndrome. Am J Med Genet C Semin Med Genet. 2010; 154C:343–354. PMID: 20803657.

20. Tan TY, Amor DJ. Tumour surveillance in Beckwith-Wiedemann syndrome and hemihyperplasia: a critical review of the evidence and suggested guidelines for local practice. J Paediatr Child Health. 2006; 42:486–490. PMID: 16925531.

21. Cohen MM Jr. Beckwith-Wiedemann syndrome: historical, clinicopathological, and etiopathogenetic perspectives. Pediatr Dev Pathol. 2005; 8:287–304. PMID: 16010495.

22. DeBaun MR, Tucker MA. Risk of cancer during the first four years of life in children from The Beckwith-Wiedemann Syndrome Registry. J Pediatr. 1998; 132(3 Pt 1):398–400. PMID: 9544889.

23. Clericuzio CL, Martin RA. Diagnostic criteria and tumor screening for individuals with isolated hemihyperplasia. Genet Med. 2009; 11:220–222. PMID: 19367194.

24. Zarate YA, Mena R, Martin LJ, Steele P, Tinkle BT, Hopkin RJ. Experience with hemihyperplasia and Beckwith-Wiedemann syndrome surveillance protocol. Am J Med Genet A. 2009; 149A:1691–1697. PMID: 19610116.

25. Waziri M, Patil SR, Hanson JW, Bartley JA. Abnormality of chromosome 11 in patients with features of Beckwith-Wiedemann syndrome. J Pediatr. 1983; 102:873–876. PMID: 6854451.

26. Weksberg R, Shuman C, Smith AC. Beckwith-Wiedemann syndrome. Am J Med Genet C Semin Med Genet. 2005; 137C:12–23. PMID: 16010676.

27. Hao Y, Crenshaw T, Moulton T, Newcomb E, Tycko B. Tumour-suppressor activity of H19 RNA. Nature. 1993; 365:764–767. PMID: 7692308.

28. Guo L, Choufani S, Ferreira J, Smith A, Chitayat D, Shuman C, et al. Altered gene expression and methylation of the human chromosome 11 imprinted region in small for gestational age (SGA) placentae. Dev Biol. 2008; 320:79–91. PMID: 18550048.

29. Tsugu A, Sakai K, Dirks PB, Jung S, Weksberg R, Fei YL, et al. Expression of p57(KIP2) potently blocks the growth of human astrocytomas and induces cell senescence. Am J Pathol. 2000; 157:919–932. PMID: 10980131.

30. Cerrato F, Vernucci M, Pedone PV, Chiariotti L, Sebastio G, Bruni CB, et al. The 5' end of the KCNQ1OT1 gene is hypomethylated in the Beckwith-Wiedemann syndrome. Hum Genet. 2002; 111:105–107. PMID: 12136243.

31. Weksberg R, Shuman C, Beckwith JB. Beckwith-Wiedemann syndrome. Eur J Hum Genet. 2010; 18:8–14. PMID: 19550435.

32. Eggermann T, Begemann M, Binder G, Spengler S. Silver-Russell syndrome: genetic basis and molecular genetic testing. Orphanet J Rare Dis. 2010; 5:19. PMID: 20573229.

33. Eggermann T. Russell-Silver syndrome. Am J Med Genet C Semin Med Genet. 2010; 154C:355–364. PMID: 20803658.

34. Eggermann T. Silver-Russell and Beckwith-Wiedemann syndromes: opposite (epi)mutations in 11p15 result in opposite clinical pictures. Horm Res. 2009; 71(Suppl 2):30–35. PMID: 19407494.