Overgrowth syndromes comprise a heterogeneous group of diseases that are characterized by excessive tissue development. Some of these syndromes may be associated with dysfunction in the receptor tyrosine kinase (RTK)/PI3K/AKT pathway, which results in an increased expression of the insulin receptor. In the current review, four overgrowth syndromes were characterized (Proteus syndrome, Klippel-Trenaunay-Weber syndrome, Madelung’s disease, and neurofibromatosis type I) and illustrated using cases from our institution. Because these syndromes have overlapping clinical manifestations and have no established genetic tests for their diagnosis, radiological methods are important contributors to the diagnosis of many of these syndromes. The correlation of genetic discoveries and molecular pathways that may contribute to the phenotypic expression is also of interest, as this may lead to potential therapeutic interventions. 1. Introduction Longitudinal growth results from multifactorial and complex processes that take place in the broader context of different genetic traits and environmental influences [1, 2]. Overgrowth syndromes comprise a heterogeneous group of disorders that lead to excessive tissue proliferation, which is characterized by a phenotype of excessive somatic and visceral growth [1–3]. A myriad of syndromes are characterized by substantial localized or asymmetric tissue overgrowth, represented by Beckwith-Wiedemann syndrome, Sotos syndrome, Proteus syndrome, Klippel-Trenaunay-Weber syndrome, Madelung’s disease, neurofibromatosis type I, Weaver syndrome, Nevo syndrome, Simpson-Golabi-Behmel syndrome, Bannayan-Riley-Ruvalcaba syndrome, Perlman syndrome, Pallister-Killian syndrome, and many other conditions. The Beckwith-Wiedemann and Sotos syndromes are the most frequent [1–4]. Overgrowth syndromes can be localized or diffuse and often manifest at birth or in the postnatal period [4]. Though most growth syndrome have a genetic basis, others such as Madelung’s disease have unknown etiology [4]. Genetic associations are already well established for some conditions including Weaver, Perlman, and Proteus syndromes [2]. The fact that Madelung’s disease tends to occur in older males and is often associated with heavy alcohol consumption in 60–90% of cases suggests that it is an acquired abnormality or more susceptible to environmental modifiers [5, 6]. Importantly, most of these syndromes lead to increased risks of cognitive disorders and cancers [7]. The frequency of cancer is well documented in some syndromes such as Proteus (20%), Sotos (2–4%), and
References
[1]
R. Visser, S. G. Kant, J. M. Wit, and M. H. Breung, “Overgrowth syndromes: from classical to new,” Pediatric Endocrinology Reviews, vol. 6, no. 3, pp. 375–394, 2009.
[2]
O. M. Neylon, G. A. Werther, and M. A. Sabin, “Overgrowth syndromes,” Current Opinion in Pediatrics, vol. 24, no. 4, pp. 505–511, 2012.
[3]
I. Bentov and H. Werner, “IGF, IGF receptor and overgrowth syndromes,” Pediatric Endocrinology Reviews, vol. 1, no. 4, pp. 352–360, 2004.
[4]
K. T. Barker and R. S. Houlston, “Overgrowth syndromes: is dysfunctional PI3-kinase signalling a unifying mechanism?” European Journal of Human Genetics, vol. 11, no. 9, pp. 665–670, 2003.
[5]
A. Tufan, R. Mercan, A. Kaya, et al., “An unusual case of Madelung's disease with multiple atypical fractures,” Case Reports in Orthopedics, vol. 2012, Article ID 180506, 3 pages, 2012.
[6]
E. Mevio, M. Sbrocca, M. Mullace, S. Viglione, and N. Mevio, “Multiple symmetric lipomatosis: a review of 3 cases,” Case Reports in Otolaryngology, vol. 2012, Article ID 910526, 4 pages, 2012.
[7]
M. M. Cohen Jr., “Overgrowth syndromes: an update,” Advances in Pediatrics, vol. 46, pp. 441–491, 1999.
[8]
R. Gracia Bouthelier and P. Lapunzina, “Follow-up and risk of tumors in overgrowth syndromes,” Journal of Pediatric Endocrinology and Metabolism, vol. 18, no. 1, pp. 1227–1235, 2005.
[9]
G. M. Mirzaa, J. Rivière, and W. B. Dobyns, “Megalencephaly syndromes and activating mutations in the PI3K-AKT pathway: MPPH and MCAP,” American Journal of Medical Genetics C: Seminars in Medical Genetics, vol. 163, no. 2, pp. 122–130, 2013.
[10]
T. L. Yuan and L. C. Cantley, “PI3K pathway alterations in cancer: variations on a theme,” Oncogene, vol. 27, no. 41, pp. 5497–5510, 2008.
[11]
K. C. Kurek, V. L. Luks, U. M. Ayturk et al., “Somatic mosaic activating mutations in PIK3CA cause CLOVES syndrome,” American Journal of Human Genetics, vol. 90, no. 6, pp. 1108–1115, 2012.
[12]
B. Baskin, S. Choufani, Y. A. Chen, et al., “High frequency of copy number variations (CNVs) in the chromosome 11p15 region in patients with Beckwith-Wiedemann syndrome,” Human Genetics, vol. 133, no. 3, pp. 321–330, 2014.
[13]
W. T. Gibson, R. L. Hood, S. H. Zhan et al., “Mutations in EZH2 cause weaver syndrome,” American Journal of Human Genetics, vol. 90, no. 1, pp. 110–118, 2012.
[14]
D. Astuti, M. R. Morris, W. N. Cooper et al., “Germline mutations in DIS3L2 cause the Perlman syndrome of overgrowth and Wilms tumor susceptibility,” Nature Genetics, vol. 44, no. 3, pp. 277–284, 2012.
[15]
G. Neri and M. Moscarda, “Overgrowth syndromes: a classification,” Endocrine Development, vol. 14, pp. 53–60, 2009.
[16]
D. Melis, R. Genesio, E. Del Giudice et al., “Selective cognitive impairment and tall stature due to chromosome 19 supernumerary ring,” Clinical Dysmorphology, vol. 21, no. 1, pp. 27–32, 2012.
[17]
S. C. Elalaoui, I. Garin, A. Sefiani, and G. Perez de Nanclares, “Maternal hypomethylation of KvDMR in a monozygotic male twin pair discordant for Beckwith-Wiedemann syndrome,” Molecular Syndromology, vol. 5, no. 1, pp. 41–46, 2014.
[18]
S. Senniappan, D. Ismail, C. Shipster, C. Beesley, and K. Hussain, “The heterogeneity of hyperinsulinaemic hypoglycaemia in 19 patients with Beckwith-Wiedemann syndrome due to KvDMR1 hypomethylation,” Journal of Pediatric Endocrinology & Metabolism, 2014.
[19]
M. J. Kaduthodil, D. S. Prasad, A. S. Lowe, A. S. Punekar, S. Yeung, and C. L. Kay, “Imaging manifestations in Proteus syndrome: an unusual multisystem developmental disorder,” British Journal of Radiology, vol. 85, no. 1017, pp. e793–e799, 2012.
[20]
H. Hamm, “Cutaneous mosaicism of lethal mutations,” American Journal of Medical Genetics, vol. 85, no. 4, pp. 342–345, 1999.
[21]
M. J. Lindhurst, J. C. Sapp, J. K. Teer et al., “A mosaic activating mutation in AKT1 associated with the proteus syndrome,” New England Journal of Medicine, vol. 365, no. 7, pp. 611–619, 2011.
[22]
C. Alves, A. X. Acosta, and M. P. Toralles, “Proteus syndrome: clinical diagnosis of a series of cases,” Indian Journal of Endocrinology and Metabolism, vol. 17, no. 6, pp. 1053–1611, 2013.
[23]
C. A. Jamis-Dow, J. Turner, L. G. Biesecker, and P. L. Choyke, “Radiologic manifestations of Proteus syndrome,” Radiographics, vol. 24, no. 4, pp. 1051–1068, 2004.
[24]
L. Biesecker, “The challenges of Proteus syndrome: diagnosis and management,” European Journal of Human Genetics, vol. 14, no. 11, pp. 1151–1157, 2006.
[25]
L. G. Biesecker, R. Happle, J. B. Mulliken, et al., “Proteus syndrome: diagnostic criteria, differential diagnosis, and patient evaluation,” American Journal of Medical Genetics, vol. 84, no. 5, pp. 389–395, 1999.
[26]
C. Y. Li, Y. L. Chang, W. C. Chen, and Y. C. Lee, “Pulmonary manifestations and management of proteus syndrome,” Journal of the Formosan Medical Association, vol. 109, no. 5, pp. 397–400, 2010.
[27]
K. M. Elsayes, C. O. Menias, J. R. Dillman, J. F. Platt, J. M. Willatt, and J. P. Heiken, “Vascular malformation and hemangiomatosis syndromes: spectrum of imaging manifestations,” American Journal of Roentgenology, vol. 190, no. 5, pp. 1291–1299, 2008.
[28]
I. Lorda-Sanchez, L. Prieto, E. Rodriguez-Pinilla, and M. L. Martinez-Frias, “Increased parental age and number of pregnancies in Klippel-Trenaunay-Weber syndrome,” Annals of Human Genetics, vol. 62, no. 3, pp. 235–239, 1998.
[29]
S. H. Cha, M. A. Romeo, and J. A. Neutze, “Visceral manifestations of Klippel-Trénaunay syndrome,” Radiographics, vol. 25, no. 6, pp. 1694–1697, 2005.
[30]
C. A. De Leon, L. R. Braun Filho, M. D. Ferrari, B. L. Guidolin, and B. J. Maffessoni, “Klippel-Trenaunay syndrome: case report,” Anais Brasileiros de Dermatologia, vol. 85, no. 1, pp. 93–96, 2010.
[31]
M. Servelle, “Klippel and Trenaunay's syndrome. 768 operated cases,” Annals of Surgery, vol. 201, no. 3, pp. 365–373, 1985.
[32]
L. A. Favorito, “Vesical hemangioma in patient with Klippel-Trenaunay-Weber syndrome,” International Braz J Urol, vol. 29, no. 2, pp. 149–150, 2003.
[33]
N. Revencu, L. M. Boon, A. Dompmartin et al., “Germline mutations in RASA1 are not found in patients with Klippel-Trenaunay syndrome or capillary malformation with limb overgrowth,” Molecular Syndromology, vol. 4, no. 4, pp. 173–178, 2013.
[34]
P. Gloviczki and D. J. Driscoll, “Klippel-Trenaunay syndrome: current management,” Phlebology, vol. 22, no. 6, pp. 291–298, 2007.
[35]
R. L. G. Flumignan, D. G. Cacione, S. I. Lopes et al., “Klippel-Trenaunay-Weber syndrome: association of operative treatment with foam sclerotherapy,” Jornal Vascular Brasileiro, vol. 10, no. 1, pp. 77–80, 2011.
[36]
A. G. Jacob, D. J. Driscoll, W. J. Shaughnessy, A. W. Stanson, R. P. Clay, and P. Gloviczki, “Klippel-Trénaunay syndrome: spectrum and management,” Mayo Clinic Proceedings, vol. 73, no. 1, pp. 28–36, 1998.
[37]
M. M. Al-Salman, “Klippel-Trenaunay Syndrome: clinical features, complications, and management,” Surgery Today, vol. 27, no. 8, pp. 735–740, 1997.
[38]
K. T. Delis, P. Gloviczki, P. W. Wennberg, T. W. Rooke, and D. J. Driscoll, “Hemodynamic impairment, venous segmental disease, and clinical severity scoring in limbs with Klippel-Trenaunay syndrome,” Journal of Vascular Surgery, vol. 45, no. 3, pp. 561–567, 2007.
[39]
M. C. Garzon, J. T. Huang, O. Enjolras, and I. J. Frieden, “Vascular malformations. Part II: associated syndromes,” Journal of the American Academy of Dermatology, vol. 56, no. 4, pp. 541–564, 2007.
[40]
V. Latessa and K. Frasier, “Case study: a minimally invasive approach to the treatment of Klippel-Trenaunay syndrome,” Journal of Vascular Nursing, vol. 25, no. 4, pp. 76–84, 2007.
[41]
G. Enzi, “Multiple symmetric lipomatosis: an updated clinical report,” Medicine, vol. 63, no. 1, pp. 56–64, 1984.
[42]
G. Enzi, C. Angelini, P. Negrin, M. Armani, S. Pierobon, and D. Fedele, “Sensory, motor, and autonomic neuropathy in patients with multiple symmetric lipomatosis,” Medicine, vol. 64, no. 6, pp. 388–393, 1985.
[43]
í. I. Shibasaki, H. I. Shibasaki, T. S. Nakamoto, F. S. Baccan, and L. S. Raposo, “Multiple symmetrical lipomatosis (Madelung's disease),” Brazilian Journal of Otorhinolaryngology, vol. 80, no. 1, pp. 90–91, 2014.
[44]
F. Y. Lin and T. L. Yang, “Madelung disease,” Canadian Medical Association Journal, vol. 185, no. 1, p. E79, 2013.
[45]
C. Plummer, P. J. Spring, R. Marotta et al., “Multiple symmetrical lipomatosis: a mitochondrial disorder of brown fat,” Mitochondrion, vol. 13, no. 4, pp. 269–276, 2013.
[46]
M. V. Vieira, R. U. Grazziotin, M. Abreu et al., “Multiple symmetrical lipomatosis (Madelung's disease): a case report,” Radiologia Brasileira, vol. 34, no. 2, pp. 119–121, 2001.
[47]
M. S. Landis, R. Etemad-Rezai, K. Shetty, and M. Goldszmidt, “Case 143: Madelung disease,” Radiology, vol. 250, no. 3, pp. 951–954, 2009.
[48]
L. P. Rodrigues and E. L. A. Melo, “Madelung's disease: a case report and literature review,” Radiologia Brasileira, vol. 43, no. 2, pp. 275–276, 2012.
[49]
B. J. Fortman, B. S. Kuszyk, B. A. Urban, and E. K. Fishman, “Neurofibromatosis type 1: a diagnostic mimicker at CT,” Radiographics, vol. 21, no. 3, pp. 601–612, 2001.
[50]
E. N. Washington, T. P. Placket, R. A. Gagliano, J. Kavolius, and D. A. Person, “Diffuse plexiform neurofibroma of the back: report of a case,” Hawaii Medical Journal, vol. 69, no. 8, pp. 191–193, 2010.
[51]
V. C. Williams, J. Lucas, M. A. Babcock, D. H. Gutmann, B. Bruce, and B. L. Maria, “Neurofibromatosis type 1 revisited,” Pediatrics, vol. 123, no. 1, pp. 124–133, 2009.
[52]
K. A. Diggs-Andrews, J. A. Brown, S. M. Gianino, J. B. Rubin, D. F. Wozniak, and D. H. Gutmann, “Sex is a major determinant of neuronal dysfunction in neurofibromatosis type 1,” Annals of Neurology, vol. 75, no. 2, pp. 309–316, 2014.
[53]
P. R. Biondetti, M. Vigo, D. Fiore, D. De Faveri, R. Ravasini, and L. Benedetti, “CT appearance of generalized von Recklinghausen neurofibromatosis,” Journal of Computer Assisted Tomography, vol. 7, no. 5, pp. 866–869, 1983.
[54]
K. P. Boyd, B. R. Korf, and A. Theos, “Neurofibromatosis type 1,” Journal of the American Academy of Dermatology, vol. 61, no. 1, pp. 1–14, 2009.
[55]
A. Ferrari, G. Bisogno, A. Macaluso et al., “Soft-tissue sarcomas in children and adolescents with neurofibromatosis type 1,” Cancer, vol. 109, no. 7, pp. 1406–1412, 2007.
