Abstract
Overgrowth syndromes are a heterogeneous group of rare disorders characterized by generalized or segmental excessive growth commonly associated with additional features, such as visceromegaly, macrocephaly and a large range of various symptoms. These syndromes are caused by either genetic or epigenetic anomalies affecting factors involved in cell proliferation and/or the regulation of epigenetic markers. Some of these conditions are associated with neurological anomalies, such as cognitive impairment or autism. Overgrowth syndromes are frequently associated with an increased risk of cancer (embryonic tumours during infancy or carcinomas during adulthood), but with a highly variable prevalence. Given this risk, syndrome-specific tumour screening protocols have recently been established for some of these conditions. Certain specific clinical traits make it possible to discriminate between different syndromes and orient molecular explorations to determine which molecular tests to conduct, despite the syndromes having overlapping clinical features. Recent advances in molecular techniques using next-generation sequencing approaches have increased the number of patients with an identified molecular defect (especially patients with segmental overgrowth). This Review discusses the clinical and molecular diagnosis, tumour risk and recommendations for tumour screening for the most prevalent generalized and segmental overgrowth syndromes.
Key points
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Overgrowth syndromes are a heterogeneous group of disorders with clinical overlap and specific clinical traits that make it possible to distinguish between them.
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Most overgrowth syndromes are caused by anomalies in factors that are implicated in the control of cell proliferation or in the control of epigenetic markers.
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Advances in the past decade have enabled the identification of mosaic molecular defects in hyperplastic tissues of patients with segmental overgrowth, particularly in the PI3K–AKT pathway.
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An increased risk of tumours is usually reported in patients with overgrowth syndromes.
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Syndrome-specific tumour screening programmes are needed on the basis of international consensus meetings.
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Strategies for molecular explorations should be based on an accurate clinical description, as the molecular defects can be genetic (mutations), cytogenetic (large rearrangements) or epigenetic.
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References
Mussa, A. et al. (Epi)genotype-phenotype correlations in Beckwith-Wiedemann syndrome. Eur. J. Hum. Genet. 24, 183–190 (2016).
Burton, G. J. & Jauniaux, E. Pathophysiology of placental-derived fetal growth restriction. Am. J. Obstet. Gynecol. 218, S745–S761 (2018).
Buchanan, T. A., Xiang, A. H. & Page, K. A. Gestational diabetes mellitus: risks and management during and after pregnancy. Nat. Rev. Endocrinol. 8, 639–649 (2012).
Tatton-Brown, K. et al. Mutations in epigenetic regulation genes are a major cause of overgrowth with intellectual disability. Am. J. Hum. Genet. 100, 725–736 (2017).
Matsuoka, S. et al. p57KIP2, a structurally distinct member of the p21CIP1 Cdk inhibitor family, is a candidate tumor suppressor gene. Genes Dev. 9, 650–662 (1995).
Stampone, E. et al. Genetic and epigenetic control of CDKN1C expression: importance in cell commitment and differentiation, tissue homeostasis and human diseases. Int. J. Mol. Sci. 19, E1055 (2018).
Giabicani, E., Netchine, I. & Brioude, F. New clinical and molecular insights into Silver-Russell syndrome. Curr. Opin. Pediatr. 28, 529–535 (2016).
Arboleda, V. A. et al. Mutations in the PCNA-binding domain of CDKN1C cause IMAGe syndrome. Nat. Genet. 44, 788–792 (2012).
Eggermann, T. et al. Prenatal molecular testing for Beckwith-Wiedemann and Silver-Russell syndromes: a challenge for molecular analysis and genetic counseling. Eur. J. Hum. Genet. 24, 784–793 (2016).
Abi Habib, W. et al. Genetic disruption of the oncogenic HMGA2-PLAG1-IGF2 pathway causes fetal growth restriction. Genet. Med. 20, 250–258 (2018).
Cheung, M. & Testa, J. R. Diverse mechanisms of AKT pathway activation in human malignancy. Curr. Cancer Drug Targets 13, 234–244 (2013).
Baron, J. et al. Short and tall stature: a new paradigm emerges. Nat. Rev. Endocrinol. 11, 735–746 (2015).
Trivellin, G. et al. Gigantism and acromegaly due to Xq26 microduplications and GPR101 mutation. N. Engl. J. Med. 371, 2363–2374 (2014).
Ben Harouch, S., Klar, A. & Falik Zaccai, T. C. INSR-related severe syndromic insulin resistance. GeneReviews https://www.ncbi.nlm.nih.gov/books/NBK476444 (updated 25 Jan 2018).
Temple, I. K. & Mackay, D. J. G. Diabetes mellitus, 6q24-related transient neonatal. GeneReviews https://www.ncbi.nlm.nih.gov/books/NBK1534 (updated 13 Sep 2018).
Nessa, A., Rahman, S. A. & Hussain, K. Hyperinsulinemic hypoglycemia - the molecular mechanisms. Front. Endocrinol. (Lausanne) 7, 29 (2016).
Albuquerque, D., Stice, E., Rodriguez-Lopez, R., Manco, L. & Nobrega, C. Current review of genetics of human obesity: from molecular mechanisms to an evolutionary perspective. Mol. Genet. Genomics 290, 1191–1221 (2015).
Kalish, J. M. et al. Nomenclature and definition in asymmetric regional body overgrowth. Am. J. Med. Genet. A 173, 1735–1738 (2017).
Beckwith, J. B. in Annual Meeting of Western Society of Pediatric Research (WSPR, Los Angeles, California, 1963).
Wiedemann, H. R. The EMG-syndrome: exomphalos, macroglossia, gigantism and disturbed carbohydrate metabolism [German]. Z. Kinderheilkd 106, 171–185 (1969).
Shuman, C., Beckwith, J. B. & Weksberg, R. Beckwith-Wiedemann syndrome. GeneReviews https://www.ncbi.nlm.nih.gov/books/NBK1394 (updated 11 Aug 2016).
Romanelli, V. et al. CDKN1C mutations in HELLP/preeclamptic mothers of Beckwith-Wiedemann Syndrome (BWS) patients. Placenta 30, 551–554 (2009).
Brioude, F. et al. CDKN1C mutation affecting the PCNA-binding domain as a cause of familial Russell Silver syndrome. J. Med. Genet. 50, 823–830 (2013).
Brioude, F. et al. Expert consensus document: clinical and molecular diagnosis, screening and management of Beckwith-Wiedemann syndrome: an international consensus statement. Nat. Rev. Endocrinol. 14, 229–249 (2018).
Eggermann, T. et al. Imprinting disorders: a group of congenital disorders with overlapping patterns of molecular changes affecting imprinted loci. Clin. Epigenetics 7, 123 (2015).
Heide, S. et al. Chromosomal rearrangements in the 11p15 imprinted region: 17 new 11p15.5 duplications with associated phenotypes and putative functional consequences. J. Med. Genet. 55, 205–213 (2018).
Kalish, J. M. et al. Clinical features of three girls with mosaic genome-wide paternal uniparental isodisomy. Am. J. Med. Genet. A 161A, 1929–1939 (2013).
Eggermann, T. et al. Clinical utility gene card for: Beckwith-Wiedemann Syndrome. Eur. J. Hum. Genet. 22, 435 (2014).
Poole, R. L. et al. Beckwith-Wiedemann syndrome caused by maternally inherited mutation of an OCT-binding motif in the IGF2/H19-imprinting control region, ICR1. Eur. J. Hum. Genet. 20, 240–243 (2012).
Abi Habib, W. et al. Extensive investigation of the IGF2/H19 imprinting control region reveals novel OCT4/SOX2 binding site defects associated with specific methylation patterns in Beckwith-Wiedemann syndrome. Hum. Mol. Genet. 23, 5763–5773 (2014).
Kagan, K. O. et al. Novel fetal and maternal sonographic findings in confirmed cases of Beckwith-Wiedemann syndrome. Prenat. Diagn. 35, 394–399 (2015).
Azzi, S. et al. Complex tissue-specific epigenotypes in Russell-Silver Syndrome associated with 11p15 ICR1 hypomethylation. Hum. Mutat. 35, 1211–1220 (2014).
Wakeling, E. L. et al. Diagnosis and management of Silver-Russell syndrome: first international consensus statement. Nat. Rev. Endocrinol. 13, 105–124 (2017).
Geoffron, S. et al. Chromosome 14q32.2 imprinted region disruption as an alternative molecular diagnosis of Silver-Russell syndrome. J. Clin. Endocrinol. Metab. 103, 2436–2446 (2018).
Mackay, D. J. et al. Hypomethylation of multiple imprinted loci in individuals with transient neonatal diabetes is associated with mutations in ZFP57. Nat. Genet. 40, 949–951 (2008).
Maupetit-Mehouas, S. et al. Simultaneous hyper- and hypomethylation at imprinted loci in a subset of patients with GNAS epimutations underlies a complex and different mechanism of multilocus methylation defect in pseudohypoparathyroidism type 1b. Hum. Mutat. 34, 1172–1180 (2013).
Mantovani, G. et al. Diagnosis and management of pseudohypoparathyroidism and related disorders: first international Consensus Statement. Nat. Rev. Endocrinol. 14, 476–500 (2018).
Poole, R. L. et al. Targeted methylation testing of a patient cohort broadens the epigenetic and clinical description of imprinting disorders. Am. J. Med. Genet. A 161A, 2174–2182 (2013).
Docherty, L. E. et al. Mutations in NLRP5 are associated with reproductive wastage and multilocus imprinting disorders in humans. Nat. Commun. 6, 8086 (2015).
Begemann, M. et al. Maternal variants in NLRP and other maternal effect proteins are associated with multilocus imprinting disturbance in offspring. J. Med. Genet. 55, 497–504 (2018).
Niemitz, E. L. & Feinberg, A. P. Epigenetics and assisted reproductive technology: a call for investigation. Am. J. Hum. Genet. 74, 599–609 (2004).
Rossignol, S. et al. The epigenetic imprinting defect of patients with Beckwith-Wiedemann syndrome born after assisted reproductive technology is not restricted to the 11p15 region. J. Med. Genet. 43, 902–907 (2006).
Maher, E. R. et al. Beckwith-Wiedemann syndrome and assisted reproduction technology (ART). J. Med. Genet. 40, 62–64 (2003).
Cox, G. F. et al. Intracytoplasmic sperm injection may increase the risk of imprinting defects. Am. J. Hum. Genet. 71, 162–164 (2002).
Cortessis, V. K. et al. Comprehensive meta-analysis reveals association between multiple imprinting disorders and conception by assisted reproductive technology. J. Assist. Reprod. Genet. 35, 943–952 (2018).
Mussa, A. et al. Assisted reproductive techniques and risk of Beckwith-Wiedemann syndrome. Pediatrics 140, e20164311 (2017).
Simpson, J. L., Landey, S., New, M. & German, J. A previously unrecognized X-linked syndrome of dysmorphia. Birth Defects Orig. Artic. Ser. 11, 18–24 (1975).
Behmel, A., Plochl, E. & Rosenkranz, W. A new X-linked dysplasia gigantism syndrome: identical with the Simpson dysplasia syndrome? Hum. Genet. 67, 409–413 (1984).
Golabi, M. & Rosen, L. A new X-linked mental retardation-overgrowth syndrome. Am. J. Med. Genet. 17, 345–358 (1984).
Sajorda, B. J., Gonzalez-Gandolfi, C. X., Hathaway, E. R. & Kalish, J. M. Simpson-Golabi-Behmel syndrome type 1. GeneReviews https://www.ncbi.nlm.nih.gov/books/NBK1219 (updated 29 Nov 2018).
Cottereau, E. et al. Phenotypic spectrum of Simpson-Golabi-Behmel syndrome in a series of 42 cases with a mutation in GPC3 and review of the literature. Am. J. Med. Genet. C Semin. Med. Genet. 163C, 92–105 (2013).
Tenorio, J. et al. Simpson-Golabi-Behmel syndrome types I and II. Orphanet J. Rare Dis. 9, 138 (2014).
Vuillaume, M. L. et al. CUGC for Simpson-Golabi-Behmel syndrome (SGBS). Eur. J. Hum. Genet. https://doi.org/10.1038/s41431-019-0339-z (2019).
Schirwani, S. et al. Duplications of GPC3 and GPC4 genes in symptomatic demale carriers of Simpson-Golabi-Behmel syndromes type 1. Eur. J. Med. Genet. https://doi.org/10.1016/j.ejmg.2018.07.022 (2018).
Pilia, G. et al. Mutations in GPC3, a glypican gene, cause the Simpson-Golabi-Behmel overgrowth syndrome. Nat. Genet. 12, 241–247 (1996).
Vuillaume, M. L. et al. Mutation update for the GPC3 gene involved in Simpson-Golabi-Behmel syndrome and review of the literature. Hum. Mutat. 39, 790–805 (2018).
Capurro, M. I. et al. Glypican-3 inhibits Hedgehog signaling during development by competing with patched for Hedgehog binding. Dev. Cell 14, 700–711 (2008).
Filmus, J. & Capurro, M. Glypican-3: a marker and a therapeutic target in hepatocellular carcinoma. FEBS J. 280, 2471–2476 (2013).
Shi, W. & Filmus, J. A patient with the Simpson-Golabi-Behmel syndrome displays a loss-of-function point mutation in GPC3 that inhibits the attachment of this proteoglycan to the cell surface. Am. J. Med. Genet. A 149A, 552–554 (2009).
Veugelers, M. et al. Mutational analysis of the GPC3/GPC4 glypican gene cluster on Xq26 in patients with Simpson-Golabi-Behmel syndrome: identification of loss-of-function mutations in the GPC3 gene. Hum. Mol. Genet. 9, 1321–1328 (2000).
Sotos, J. F., Dodge, P. R., Muirhead, D., Crawford, J. D. & Talbot, N. B. Cerebral gigantism in childhood. a syndrome of excessively rapid growth and acromegalic features and a nonprogressive neurologic disorder. N. Engl. J. Med. 271, 109–116 (1964).
Tatton-Brown, K. et al. Genotype-phenotype associations in Sotos syndrome: an analysis of 266 individuals with NSD1 aberrations. Am. J. Hum. Genet. 77, 193–204 (2005).
Tatton-Brown, K., Cole, T. R. P. & Rahman, N. Sotos syndrome. GeneReviews https://www.ncbi.nlm.nih.gov/books/NBK1479 (updated 19 Nov 2015).
Lane, C., Milne, E. & Freeth, M. Cognition and behaviour in Sotos syndrome: a systematic review. PLOS ONE 11, e0149189 (2016).
Lane, C., Milne, E. & Freeth, M. Characteristics of autism spectrum disorder in Sotos syndrome. J. Autism Dev. Disord. 47, 135–143 (2017).
Nicita, F. et al. Seizures and epilepsy in Sotos syndrome: analysis of 19 caucasian patients with long-term follow-up. Epilepsia 53, e102–e105 (2012).
Cole, T. R. & Hughes, H. E. Sotos syndrome: a study of the diagnostic criteria and natural history. J. Med. Genet. 31, 20–32 (1994).
Kurotaki, N. et al. Haploinsufficiency of NSD1 causes Sotos syndrome. Nat. Genet. 30, 365–366 (2002).
Rayasam, G. V. et al. NSD1 is essential for early post-implantation development and has a catalytically active SET domain. EMBO J. 22, 3153–3163 (2003).
Luscan, A. et al. Mutations in SETD2 cause a novel overgrowth condition. J. Med. Genet. 51, 512–517 (2014).
Tlemsani, C. et al. SETD2 and DNMT3A screen in the Sotos-like syndrome French cohort. J. Med. Genet. 53, 743–751 (2016).
Almuriekhi, M. et al. Loss-of-function mutation in APC2 causes Sotos syndrome features. Cell Rep. 15, 139–134 (2015).
Edmunds, J. W., Mahadevan, L. C. & Clayton, A. L. Dynamic histone H3 methylation during gene induction: HYPB/Setd2 mediates all H3K36 trimethylation. EMBO J. 27, 406–420 (2008).
Otani, J. et al. Structural basis for recognition of H3K4 methylation status by the DNA methyltransferase 3A ATRX-DNMT3-DNMT3L domain. EMBO Rep. 10, 1235–1241 (2009).
O’Roak, B. J. et al. Multiplex targeted sequencing identifies recurrently mutated genes in autism spectrum disorders. Science 338, 1619–1622 (2012).
Iossifov, I. et al. The contribution of de novo coding mutations to autism spectrum disorder. Nature 515, 216–221 (2014).
Lumish, H. S., Wynn, J., Devinsky, O. & Chung, W. K. Brief report: SETD2 mutation in a child with autism, intellectual disabilities and epilepsy. J. Autism Dev. Disord. 45, 3764–3770 (2015).
Tatton-Brown, K. et al. Mutations in the DNA methyltransferase gene DNMT3A cause an overgrowth syndrome with intellectual disability. Nat. Genet. 46, 385–388 (2014).
Xin, B. et al. Novel DNMT3A germline mutations are associated with inherited Tatton-Brown-Rahman syndrome. Clin. Genet. 91, 623–628 (2017).
Kosaki, R., Terashima, H., Kubota, M. & Kosaki, K. Acute myeloid leukemia-associated DNMT3A p. Arg882His mutation in a patient with tatton-Brown-Rahman overgrowth syndrome as a constitutional mutation. Am. J. Med. Genet. A 173, 250–253 (2017).
Tatton-Brown, K. et al. The Tatton-Brown-Rahman syndrome: a clinical study of 55 individuals with de novo constitutive DNMT3A variants. Wellcome Open Res. 3, 46 (2018).
Malan, V. et al. Distinct effects of allelic NFIX mutations on nonsense-mediated mRNA decay engender either a Sotos-like or a Marshall-Smith syndrome. Am. J. Hum. Genet. 87, 189–198 (2010).
Klaassens, M. et al. Malan syndrome: Sotos-like overgrowth with de novo NFIX sequence variants and deletions in six new patients and a review of the literature. Eur. J. Hum. Genet. 23, 610–615 (2015).
Martinez, F. et al. Novel mutations of NFIX gene causing Marshall-Smith syndrome or Sotos-like syndrome: one gene, two phenotypes. Pediatr. Res. 78, 533–539 (2015).
Bateman, J. F., Boot-Handford, R. P. & Lamande, S. R. Genetic diseases of connective tissues: cellular and extracellular effects of ECM mutations. Nat. Rev. Genet. 10, 173–183 (2009).
Mirzaa, G. et al. PIK3CA-associated developmental disorders exhibit distinct classes of mutations with variable expression and tissue distribution. JCI Insight 1, e87623 (2016).
Tatton-Brown, K. et al. Weaver syndrome and EZH2 mutations: clarifying the clinical phenotype. Am. J. Med. Genet. A 161A, 2972–2980 (2013).
Cao, R. et al. Role of histone H3 lysine 27 methylation in polycomb-group silencing. Science 298, 1039–1043 (2002).
Cohen, A. S. & Gibson, W. T. EED-associated overgrowth in a second male patient. J. Hum. Genet. 61, 831–834 (2016).
Cohen, A. S. et al. A novel mutation in EED associated with overgrowth. J. Hum. Genet. 60, 339–342 (2015).
Cooney, E., Bi, W., Schlesinger, A. E., Vinson, S. & Potocki, L. Novel EED mutation in patient with Weaver syndrome. Am. J. Med. Genet. A 173A, 541–545 (2017).
Neri, G., Martini-Neri, M. E., Katz, B. E. & Opitz, J. M. The Perlman syndrome: familial renal dysplasia with Wilms tumor, fetal gigantism and multiple congenital anomalies. Am. J. Med. Genet. 19, 195–207 (1984).
Alessandri, J. L. et al. Perlman syndrome: report, prenatal findings and review. Am. J. Med. Genet. A 146A, 2532–2537 (2008).
Astuti, D. et al. Germline mutations in DIS3L2 cause the Perlman syndrome of overgrowth and Wilms tumor susceptibility. Nat. Genet. 44, 277–284 (2012).
Labno, A. et al. Perlman syndrome nuclease DIS3L2 controls cytoplasmic non-coding RNAs and provides surveillance pathway for maturing snRNAs. Nucleic Acids Res. 44, 10437–10453 (2016).
Janku, F., Yap, T. A. & Meric-Bernstam, F. Targeting the PI3K pathway in cancer: are we making headway? Nat. Rev. Clin. Oncol. 15, 273–291 (2018).
Pilarski, R. et al. Cowden syndrome and the PTEN hamartoma tumor syndrome: systematic review and revised diagnostic criteria. J. Natl Cancer Inst. 105, 1607–1616 (2013).
Keppler-Noreuil, K. M. et al. Clinical delineation and natural history of the PIK3CA-related overgrowth spectrum. Am. J. Med. Genet. A 164A, 1713–1733 (2014).
Biesecker, L. G. & Sapp, J. C. Proteus syndrome. GeneReviews https://www.ncbi.nlm.nih.gov/books/NBK99495 (updated 10 Jan 2019).
Mirzaa, G., Conway, R., Graham, J. M. Jr & Dobyns, W. B. PIK3CA-related segmental overgrowth. GeneReviews https://www.ncbi.nlm.nih.gov/books/NBK153722 (updated 15 Aug 2013).
Michel, M. E. et al. Causal somatic mutations in urine DNA from persons with the CLOVES subgroup of the PIK3CA-related overgrowth spectrum. Clin. Genet. 93, 1075–1080 (2018).
Kuentz, P. et al. Molecular diagnosis of PIK3CA-related overgrowth spectrum (PROS) in 162 patients and recommendations for genetic testing. Genet. Med. 19, 989–997 (2017).
Nathan, N., Keppler-Noreuil, K. M., Biesecker, L. G., Moss, J. & Darling, T. N. Mosaic disorders of the PI3K/PTEN/AKT/TSC/mTORC1 signaling pathway. Dermatol. Clin. 35, 51–60 (2017).
Lindhurst, M. J. et al. A mosaic activating mutation in AKT1 associated with the Proteus syndrome. N. Engl. J. Med. 365, 611–619 (2011).
Hussain, K. et al. An activating mutation of AKT2 and human hypoglycemia. Science 334, 474 (2011).
Zhou, X. et al. Association of germline mutation in the PTEN tumour suppressor gene and Proteus and Proteus-like syndromes. Lancet 358, 210–211 (2001).
Biesecker, L. G., Rosenberg, M. J., Vacha, S., Turner, J. T. & Cohen, M. M. PTEN mutations and proteus syndrome. Lancet 358, 2079–2080 (2001).
Riviere, J. B. et al. De novo germline and postzygotic mutations in AKT3, PIK3R2 and PIK3CA cause a spectrum of related megalencephaly syndromes. Nat. Genet. 44, 934–940 (2012).
Mirzaa, G. et al. De novo CCND2 mutations leading to stabilization of cyclin D2 cause megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome. Nat. Genet. 46, 510–515 (2014).
Kratz, C. P. et al. Cancer screening recommendations for individuals with Li-Fraumeni syndrome. Clin. Cancer Res. 23, e38–e45 (2017).
Chen, S. & Parmigiani, G. Meta-analysis of BRCA1 and BRCA2 penetrance. J. Clin. Oncol. 25, 1329–1333 (2007).
Scott, J. et al. Insulin-like growth factor-II gene expression in Wilms’ tumour and embryonic tissues. Nature 317, 260–262 (1985).
Gicquel, C. et al. Rearrangements at the 11p15 locus and overexpression of insulin-like growth factor-II gene in sporadic adrenocortical tumors. J. Clin. Endocrinol. Metab. 78, 1444–1453 (1994).
Akmal, S. N., Yun, K., MacLay, J., Higami, Y. & Ikeda, T. Insulin-like growth factor 2 and insulin-like growth factor binding protein 2 expression in hepatoblastoma. Hum. Pathol. 26, 846–851 (1995).
Taniguchi, T., Sullivan, M. J., Ogawa, O. & Reeve, A. E. Epigenetic changes encompassing the IGF2/H19 locus associated with relaxation of IGF2 imprinting and silencing of H19 in Wilms tumor. Proc. Natl Acad. Sci. USA 92, 2159–2163 (1995).
Rainier, S., Dobry, C. J. & Feinberg, A. P. Loss of imprinting in hepatoblastoma. Cancer Res. 55, 1836–1838 (1995).
Mussa, A. et al. Cancer risk in Beckwith-Wiedemann Syndrome: a systematic review and meta-analysis outlining a novel (epi)genotype specific histotype targeted screening protocol. J. Pediatr. 176, 142–149 (2016).
Maas, S. M. et al. Phenotype, cancer risk, and surveillance in Beckwith-Wiedemann syndrome depending on molecular genetic subgroups. Am. J. Med. Genet. A 170A, 2248–2260 (2016).
Brioude, F. et al. Revisiting Wilms tumour surveillance in Beckwith-Wiedemann syndrome with IC2 methylation loss, reply. Eur. J. Hum. Genet. 26, 471–472 (2018).
Kalish, J. M. et al. Surveillance recommendations for children with overgrowth syndromes and predisposition to Wilms tumors and hepatoblastoma. Clin. Cancer Res. 23, e115–e122 (2017).
Lapunzina, P. Risk of tumorigenesis in overgrowth syndromes: a comprehensive review. Am. J. Med. Genet. C Semin. Med. Genet. 137C, 53–71 (2005).
Bennett, R. L., Swaroop, A., Troche, C. & Licht, J. D. The role of nuclear receptor-binding SET domain family histone lysine methyltransferases in cancer. Cold Spring Harb. Perspect. Med. 7, a026708 (2017).
Nakagawa, M. & Kitabayashi, I. Oncogenic roles of enhancer of zeste homolog 1/2 in hematological malignancies. Cancer Sci. 109, 2342–2348 (2018).
Villani, A. et al. Recommendations for cancer surveillance in individuals with RASopathies and other rare genetic conditions with increased cancer risk. Clin. Cancer Res. 23, e83–e90 (2017).
Mester, J. & Eng, C. When overgrowth bumps into cancer: the PTEN-opathies. Am. J. Med. Genet. C Semin. Med. Genet. 163C, 114–121 (2013).
Smith, J. R. et al. Thyroid nodules and cancer in children with PTEN hamartoma tumor syndrome. J. Clin. Endocrinol. Metab. 96, 34–37 (2011).
Schultz, K. A. P. et al. PTEN, DICER1, FH, and their associated tumor susceptibility syndromes: clinical features, genetics, and surveillance recommendations in childhood. Clin. Cancer Res. 23, e76–e82 (2017).
Daly, M. B. et al. NCCN guidelines insights: genetic/familial high-risk assessment: breast and ovarian, version 2.2017. J. Natl Compr. Canc. Netw. 15, 9–20 (2017).
Gripp, K. W. et al. Nephroblastomatosis or Wilms tumor in a fourth patient with a somatic PIK3CA mutation. Am. J. Med. Genet. A 170A, 2559–2569 (2016).
Baujat, G. et al. Clinical and molecular overlap in overgrowth syndromes. Am. J. Med. Genet. C Semin. Med. Genet. 137C, 4–11 (2005).
Baujat, G. et al. Paradoxical NSD1 mutations in Beckwith-Wiedemann syndrome and 11p15 anomalies in Sotos syndrome. Am. J. Hum. Genet. 74, 715–720 (2004).
Chang, F. et al. Molecular diagnosis of mosaic overgrowth syndromes using a custom-designed next-generation sequencing panel. J. Mol. Diagn. 19, 613–624 (2017).
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Glossary
- Macrosomia
-
Fetal macrosomia has been defined in several different ways, including birthweight of 4,000–4,500 g (8 lb 13 oz to 9 lb 15 oz) or >90th percentile for gestational age after correcting for neonatal sex and ethnicity. On the basis of these definitions, macrosomia affects 1–10% of all pregnancies. A diagnosis of fetal macrosomia can be made only by measuring birthweight after delivery.
- Exomphalos
-
A midline anterior incomplete closure of the abdominal wall in which there is herniation of the abdominal viscera into the base of the abdominal cord (also known as omphalocele).
- Macroglossia
-
Increased length and width of the tongue.
- Lateralized overgrowth
-
Overgrowth of only one side of the body (also known as hemihypertrophy).
- Naevus flammeus
-
A congenital vascular malformation consisting of superficial and deep dilated capillaries in the skin that result in a reddish to purplish discolouration of the skin.
- Visceromegaly
-
Enlargement of the internal organs in the abdomen, including the liver, spleen, stomach, kidneys or pancreas.
- Uniparental disomy
-
(UPD). The inheritance of two homologous chromosomes from the same parent. These genetic anomalies arise from errors in meiosis and/or mitosis and can occur independently or in combination.
- Assisted reproductive technologies
-
Consist of procedures that involve the in vitro handling of both human oocytes and sperm, or of embryos, with the objective of establishing a pregnancy.
- Diastasis recti
-
A separation of the rectus abdominis muscle into right and left halves (which are normally joined at the midline at the linea alba).
- Pectus excavatum
-
A defect of the chest wall characterized by a depression of the sternum, giving the chest (pectus) a caved-in (excavatum) appearance.
- Postaxial polydactyly
-
A form of polydactyly in which the extra digit or digits are localized on the side of the fifth finger or fifth toe.
- Genu varum
-
A positional abnormality marked by outward bowing of the legs in which the knees stay wide apart when a person stands with the feet and ankles together.
- Genu valgum
-
A positional abnormality in which the legs angle inward, such that the knees are close together and the ankles are far apart.
- Microretrognathism
-
A form of developmental hypoplasia of the mandible in which the mandible is mislocalized posteriorly.
- Hemimegalencephaly
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Enlargement of all or parts of one cerebral hemisphere.
- Polymicrogyria
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A congenital abnormality of the cerebral hemisphere characterized by an excessive number of small gyri (convolutions) on the surface of the brain.
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Brioude, F., Toutain, A., Giabicani, E. et al. Overgrowth syndromes — clinical and molecular aspects and tumour risk. Nat Rev Endocrinol 15, 299–311 (2019). https://doi.org/10.1038/s41574-019-0180-z
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DOI: https://doi.org/10.1038/s41574-019-0180-z
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