Overgrowth syndromes
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Overgrowth syndromes are a heterogeneous group of rare developmental disorders characterised by generalised or segmental excessive growth, often accompanied by developmental delay or intellectual disability, distinctive facial features, and an increased risk of embryonal tumours in some conditions.
Fetal and postnatal growth are regulated by a complex interplay of genetic, epigenetic, endocrine, and metabolic factors that coordinate growth, development, and physiological adaptation throughout early life.
Overgrowth is defined by a height and/or occipitofrontal circumference of at least two standard deviations above the mean for age and sex – at some point in childhood. Onset may be prenatal or postnatal, and the excess may be generalised or confined to one body segment. In individuals with epigenetic or genetic forms of overgrowth, additional features are commonly observed, including dysmorphic characteristics and cognitive or behavioral abnormalities.
The largest overgrowth subgroup characterised by prenatal-onset generalised overgrowth, developmental impairment, and a distinctive phenotype, include , , and Tatton-Brown-Rahman syndrome. The second group comprises segmental overgrowth syndromes, e.g., PTEN– related or PIK3CA– related syndromes, caused by postzygotic variants, resulting in mosaic overgrowth with lateralised limb or trunk enlargement, macrodactyly, vascular malformations, and epidermal nevi. Phenotypic severity depends on the timing and extent of the mutant clone.
Epidemiological data on overgrowth syndromes are limited, particularly regarding age- and sex-specific incidence. Beckwith–Wiedemann syndrome is the most prevalent overgrowth syndrome, affecting about 1 in 10,500 births; however, its prevalence may be underestimated because of mild or incomplete phenotypes. has an estimated birth prevalence of about 1 in 14,000, while for most of the remaining conditions no reliable data exists, so a figure should not be quoted gene by gene.
The genetic basis of overgrowth syndromes is highly heterogeneous, involving genes that regulate chromatin structure and epigenetic modification, histone and DNA methylation, PI3K-AKT-mTOR signaling, imprinted growth control at 11p15.5, transcriptional and post-transcriptional processes and others.
Most conditions are autosomal dominant with a de novo variant in the majority, so the recurrence risk for parents is low but not zero because of possible gonadal mosaicism. Some genes are X-linked, like GPC3, MED12, BRWD3, OFD1, UPF3B and PIGA. And some are autosomal recessive like DIS3L2, HERC1, STRADA, TMEM94. CDKN1C is imprinted, so a pathogenic variant causes disease when transmitted by the mother and not by the father. The activating PI3K-AKT-mTOR variants are frequently postzygotic and confined to affected tissue, so the condition is sporadic and the recurrence risk is not increased.
Overgrowth is identified by serial measurement of height, weight and occipitofrontal circumference against population growth references, supplemented where indicated by bone age assessment, abdominal ultrasound and brain imaging. The diagnostic yield of sequencing is primarily constrained by two limitations. In segmental overgrowth the variant is mosaic and often absent from blood, so affected tissue analysed at high read depth is required and a negative blood result does not exclude the diagnosis. Second, sequence analysis does not detect the imprinting and methylation defects at 11p15.5 behind most Beckwith-Wiedemann syndrome, where CDKN1C variants explain only about 5% of sporadic cases; first-line testing there is methylation analysis, requested separately. A confirmed diagnosis assigns the entity, defines the recurrence risk and sets any entity-specific surveillance.
Main differential diagnoses include:
- (FBN1) presents with tall stature and a marfanoid habitus but is distinguished by aortic root dilatation and ectopia lentis.
- (47,XXY) is the commonest primary disorder associated with tall stature in childhood and is diagnosed by karyotyping or chromosomal microarray.
- Mosaic arise from postzygotic activating variants in RAS pathway genes and can produce segmental overgrowth with vascular malformations and epidermal naevi, closely mimicking the mosaic PI3K-AKT-mTOR disorders; they likewise require analysis of affected tissue.
Genetic testing establishes the specific diagnosis underlying an overgrowth presentation and provides the basis for genetic counselling. Because the tumour risk here is determined by the molecular subtype rather than the clinical impression, a confirmed result allows entity-specific surveillance to be started, adjusted or safely omitted, which the treating physicians decide with the family. Where a familial variant is known, predictive testing can be offered to at-risk relatives.
- Brioude F, Toutain A, Giabicani E, Cottereau E, Cormier-Daire V, Netchine I. Overgrowth syndromes – clinical and molecular aspects and tumour risk. Nat Rev Endocrinol. 2019;15(5):299-311. doi: 10.1038/s41574-019-0180-z. PMID: .
- Tatton-Brown K, Loveday C, Yost S, Clarke M, Ramsay E, Zachariou A, et al. Mutations in Epigenetic Regulation Genes Are a Major Cause of Overgrowth with Intellectual Disability. Am J Hum Genet. 2017;100(5):725-736. doi: 10.1016/j.ajhg.2017.03.010. PMID: .
- Ocansey S, Cole TRP, Rahman N, Tatton-Brown K. Sotos Syndrome. In: GeneReviews [Internet]. Seattle (WA): University of Washington, Seattle. Bookshelf ID: NBK1479. Last revised 5 June 2025. PMID: . Available from:
- Ocansey S, Tatton-Brown K. EZH2-Related Overgrowth. In: GeneReviews [Internet]. Seattle (WA): University of Washington, Seattle. Bookshelf ID: NBK148820. Last revised 26 June 2025. PMID: . Available from:
- Keppler-Noreuil KM, Parker VE, Darling TN, Martinez-Agosto JA. Somatic overgrowth disorders of the PI3K/AKT/mTOR pathway & therapeutic strategies. Am J Med Genet C Semin Med Genet. 2016;172(4):402-421. doi: 10.1002/ajmg.c.31531. PMID: .
- Mussa A, Carli D, Cardaropoli S, Ferrero GB, Resta N. Lateralized and Segmental Overgrowth in Children. Cancers (Basel). 2021;13(24):6166. doi: 10.3390/cancers13246166. PMID: .
- Mirzaa G. MPPH Syndrome. In: GeneReviews [Internet]. Seattle (WA): University of Washington, Seattle. Bookshelf ID: NBK396098. Last revised 28 July 2022. PMID: . Available from:
- Brioude F, Kalish JM, Mussa A, Foster AC, Bliek J, Ferrero GB, et al. Expert consensus document: Clinical and molecular diagnosis, screening and management of Beckwith-Wiedemann syndrome: an international consensus statement. Nat Rev Endocrinol. 2018;14(4):229-249. doi: 10.1038/nrendo.2017.166. PMID: .
- Harju S, Saari A, Sund R, Sankilampi U. Epidemiology of disorders associated with tall stature in childhood: A 20-year birth cohort study. PLoS One. 2025;20(4):e0321798. doi: 10.1371/journal.pone.0321798. PMID: .
- Kamien B, Ronan A, Poke G, Sinnerbrink I, Baynam G, Ward M, et al. A Clinical Review of Generalized Overgrowth Syndromes in the Era of Massively Parallel Sequencing. Mol Syndromol. 2018;9(2):70-82. doi: 10.1159/000484532. PMID: .
- Parra A, Rabin R, Pappas J, Pascual P, Cazalla M, Arias P, et al. Clinical Heterogeneity and Different Phenotypes in Patients with SETD2 Variants: 18 New Patients and Review of the Literature. Genes (Basel). 2023;14(6):1179. doi: 10.3390/genes14061179. PMID: .
- Chong JX, Yu JH, Lorentzen P, Park KM, Jamal SM, Tabor HK, et al. Gene discovery for Mendelian conditions via social networking: de novo variants in KDM1A cause developmental delay and distinctive facial features. Genet Med. 2016;18(8):788-795. doi: 10.1038/gim.2015.161. PMID: .
- Burkart S, Spanjaard M, Kaufmann L, Hinderhofer K, Schaaf CP, Ries M, et al. Phenotypical and Genotypical Expansion of Autosomal-Dominant KDM1A-Related Neurodevelopmental Disorder Spectrum: A Case Report. Am J Med Genet A. 2025;197(11):e64144. doi: 10.1002/ajmg.a.64144. PMID: .
- Mirzaa G, Graham JM Jr, Keppler-Noreuil K. PIK3CA-Related Overgrowth Spectrum. In: GeneReviews [Internet]. Seattle (WA): University of Washington, Seattle. Bookshelf ID: NBK153722. Last revised 6 April 2023. PMID: . Available from:
- Tramontana T, Yehia L. PTEN Hamartoma Tumor Syndrome. In: GeneReviews [Internet]. Seattle (WA): University of Washington, Seattle. Bookshelf ID: NBK1488. Last revised 28 July 2026. PMID: . Available from:
- Parker WE, Orlova KA, Parker WH, Birnbaum JF, Krymskaya VP, Goncharov DA, et al. Rapamycin prevents seizures after depletion of STRADA in a rare neurodevelopmental disorder. Sci Transl Med. 2013;5(182):182ra53. doi: 10.1126/scitranslmed.3005271. PMID: .
- Shuman C, Kalish JM, Weksberg R. Beckwith-Wiedemann Syndrome. In: GeneReviews [Internet]. Seattle (WA): University of Washington, Seattle. Bookshelf ID: NBK1394. Last revised 21 September 2023. PMID: . Available from:
- Arboleda VA, Lee H, Parnaik R, Fleming A, Banerjee A, Ferraz-de-Souza B, et al. Mutations in the PCNA-binding domain of CDKN1C cause IMAGe syndrome. Nat Genet. 2012;44(7):788-792. doi: 10.1038/ng.2275. PMID: .
- Cordeddu V, Redeker B, Stellacci E, Jongejan A, Fragale A, Bradley TE, et al. Mutations in ZBTB20 cause Primrose syndrome. Nat Genet. 2014;46(8):815-817. doi: 10.1038/ng.3035. PMID: .
- Lyons MJ. MED12-Related Disorders. In: GeneReviews [Internet]. Seattle (WA): University of Washington, Seattle. Bookshelf ID: NBK1676. Last revised 12 August 2021. PMID: . Available from:
- Tarpey PS, Raymond FL, Nguyen LS, Rodriguez J, Hackett A, Vandeleur L, et al. Mutations in UPF3B, a member of the nonsense-mediated mRNA decay complex, cause syndromic and nonsyndromic mental retardation. Nat Genet. 2007;39(9):1127-1133. doi: 10.1038/ng2100. PMID: .
- Astuti D, Morris MR, Cooper WN, Staals RH, Wake NC, Fews GA, et al. Germline mutations in DIS3L2 cause the Perlman syndrome of overgrowth and Wilms tumor susceptibility. Nat Genet. 2012;44(3):277-284. doi: 10.1038/ng.1071. PMID: .
- Nisbet AF, Hathaway ER, Kalish JM. Simpson-Golabi-Behmel Syndrome Type 1. In: GeneReviews [Internet]. Seattle (WA): University of Washington, Seattle. Bookshelf ID: NBK1219. Last revised 14 November 2024. PMID: . Available from:
- Budny B, Chen W, Omran H, Fliegauf M, Tzschach A, Wisniewska M, et al. A novel X-linked recessive mental retardation syndrome comprising macrocephaly and ciliary dysfunction is allelic to oral-facial-digital type I syndrome. Hum Genet. 2006;120(2):171-178. doi: 10.1007/s00439-006-0210-5. PMID: .
- Fauth C, Steindl K, Toutain A, Farrell S, Witsch-Baumgartner M, Karall D, et al. A recurrent germline mutation in the PIGA gene causes Simpson-Golabi-Behmel syndrome type 2. Am J Med Genet A. 2016;170A(2):392-402. doi: 10.1002/ajmg.a.37452. PMID: .
- Min R, Abbink TEM, van der Knaap MS. Megalencephalic Leukoencephalopathy with Subcortical Cysts. In: GeneReviews [Internet]. Seattle (WA): University of Washington, Seattle. Bookshelf ID: NBK1535. Last revised 27 July 2023. PMID: . Available from:
- Douglas J, Cilliers D, Coleman K, Tatton-Brown K, Barker K, Bernhard B, et al. Mutations in RNF135, a gene within the NF1 microdeletion region, cause phenotypic abnormalities including overgrowth. Nat Genet. 2007;39(8):963-965. doi: 10.1038/ng2083. PMID: .
- Stephen J, Maddirevula S, Nampoothiri S, Burke JD, Herzog M, Shukla A, et al. Bi-allelic TMEM94 Truncating Variants Are Associated with Neurodevelopmental Delay, Congenital Heart Defects, and Distinct Facial Dysmorphism. Am J Hum Genet. 2018;103(6):948-967. doi: 10.1016/j.ajhg.2018.11.001. PMID: .
- Imagawa E, Seyama R, Aoi H, Uchiyama Y, Marcarini BG, Furquim I, et al. Imagawa-Matsumoto syndrome: SUZ12-related overgrowth disorder. Clin Genet. 2023;103(4):383-391. doi: 10.1111/cge.14296. PMID: .
- Dietz H. FBN1-Related Marfan Syndrome. In: GeneReviews [Internet]. Seattle (WA): University of Washington, Seattle. Bookshelf ID: NBK1335. Last revised 17 February 2022. PMID: . Available from:
- Gravholt CH, Chang S, Wallentin M, Fedder J, Moore P, Skakkebaek A. Klinefelter Syndrome: Integrating Genetics, Neuropsychology, and Endocrinology. Endocr Rev. 2018;39(4):389-423. doi: 10.1210/er.2017-00212. PMID: .
- Schmidt VF, Wieland I, Wohlgemuth WA, Ricke J, Wildgruber M, Zenker M. Mosaic RASopathy due to KRAS variant G12D with segmental overgrowth and associated peripheral vascular malformations. Am J Med Genet A. 2021;185(10):3122-3128. doi: 10.1002/ajmg.a.62386. PMID: .
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