Neurocutaneous Manifestations of Genetic Mosaicism

Abstract

Genetic mosaicism is defined as the presence of two or more genetically distinct cell populations in a single individual. Ever more disorders are found to be manifestations of mosaicism and together constitute a significant proportion of the morbidity confronting pediatric specialists. An emerging category is that of overgrowth syndromes with skin manifestations and neurological or developmental abnormalities, such as the well-known Proteus syndrome. In recent years, we have seen dramatic advances in our understanding of these disorders and we now know the genetic basis of many of them. This has profound consequences for diagnosis, counselling, and even treatment, with therapies targeted to specific pathways becoming available for clinical use. Recognizing such overgrowth syndromes, therefore, is more important than ever. Fortunately, their skin manifestations can provide important diagnostic clues when evaluated in the entire phenotypic context. In this review, I provide an overview of the most frequently seen mosaic neurocutaneous phenotypes and discuss their molecular basis.

Keywords

mosaicism - skin - brain - overgrowth - intellectual disability

• References

• 1 Happle R. Cutaneous manifestation of lethal genes. Hum Genet 1986; 72 (3) 280
• 2 Findlay GH, Moores PP. Pigment anomalies of the skin in the human chimaera: their relation to systematized naevi. Br J Dermatol 1980; 103 (5) 489-498
• 3 Pollock PM, Harper UL, Hansen KS , et al. High frequency of BRAF mutations in nevi. Nat Genet 2003; 33 (1) 19-20
• 4 Logié A, Dunois-Lardé C, Rosty C , et al. Activating mutations of the tyrosine kinase receptor FGFR3 are associated with benign skin tumors in mice and humans. Hum Mol Genet 2005; 14 (9) 1153-1160
• 5 Vreeburg M, van Steensel MAM. Genodermatoses caused by genetic mosaicism. Eur J Pediatr 2012; 171 (12) 1725-1735
• 6 Happle R. Lyonization and the lines of Blaschko. Hum Genet 1985; 70 (3) 200-206
• 7 Happle R. Lethal genes surviving by mosaicism: a possible explanation for sporadic birth defects involving the skin. J Am Acad Dermatol 1987; 16 (4) 899-906
• 8 Happle R. What is a nevus? A proposed definition of a common medical term. Dermatology 1995; 191 (1) 1-5
• 9 Lapidot T, Sirard C, Vormoor J , et al. A cell initiating human acute myeloid leukaemia after transplantation into SCID mice. Nature 1994; 367 (6464) 645-648
• 10 Kobilka BK. G protein coupled receptor structure and activation. . Biochim Biophys Acta 2007; 1768 (4) 794-807
• 11 Weinstein LS, Shenker A, Gejman PV, Merino MJ, Friedman E, Spiegel AM. Activating mutations of the stimulatory G protein in the McCune-Albright syndrome. N Engl J Med 1991; 325 (24) 1688-1695
• 12 Palmisano I, Bagnato P, Palmigiano A , et al. The ocular albinism type 1 protein, an intracellular G protein-coupled receptor, regulates melanosome transport in pigment cells. Hum Mol Genet 2008; 17 (22) 3487-3501
• 13 Comi AM. Update on Sturge-Weber syndrome: diagnosis, treatment, quantitative measures, and controversies. Lymphat Res Biol 2007; 5 (4) 257-264
• 14 Waelchli R, Aylett SE, Robinson K, Chong WK, Martinez AE, Kinsler VA. New vascular classification of port-wine stains: improving prediction of Sturge-Weber risk. Br J Dermatol 2014; 171 (4) 861-867
• 15 Shirley MD, Tang H, Gallione CJ , et al. Sturge-Weber syndrome and port-wine stains caused by somatic mutation in GNAQ. N Engl J Med 2013; 368 (21) 1971-1979
• 16 Van Raamsdonk CD, Bezrookove V, Green G , et al. Frequent somatic mutations of GNAQ in uveal melanoma and blue naevi. Nature 2009; 457 (7229) 599-602
• 17 Fernández-Guarino M, Boixeda P, de Las Heras E, Aboin S, García-Millán C, Olasolo PJ. Phakomatosis pigmentovascularis: clinical findings in 15 patients and review of the literature. J Am Acad Dermatol 2008; 58 (1) 88-93
• 18 Vissers W, Van Steensel M, Steijlen P, Renier W, Van De Kerkhof P, Van Der Vleuten C. Klippel-Trenaunay syndrome and Sturge-Weber syndrome: variations on a theme?. Eur J Dermatol 2003; 13 (3) 238-241
• 19 Oduber CEU, van der Horst CMAM, Sillevis Smitt JH , et al. A proposal for classification of entities combining vascular malformations and deregulated growth. Eur J Med Genet 2011; 54 (3) 262-271
• 20 Happle R, Hoffmann R, Restano L, Caputo R, Tadini G. Phacomatosis pigmentokeratotica: a melanocytic-epidermal twin nevus syndrome. Am J Med Genet 1996; 65 (4) 363-365
• 21 Groesser L, Herschberger E, Sagrera A , et al. Phacomatosis pigmentokeratotica is caused by a postzygotic HRAS mutation in a multipotent progenitor cell. J Invest Dermatol 2013; 133 (8) 1998-2003
• 22 Brandling-Bennett HA, Morel KD. Epidermal nevi. Pediatr Clin North Am 2010; 57 (5) 1177-1198
• 23 Moody MN, Landau JM, Goldberg LH. Nevus sebaceous revisited. Pediatr Dermatol 2012; 29 (1) 15-23
• 24 Aoki Y, Niihori T, Kawame H , et al. Germline mutations in HRAS proto-oncogene cause Costello syndrome. Nat Genet 2005; 37 (10) 1038-1040
• 25 Søvik O, Schubbert S, Houge G , et al. De novo HRAS and KRAS mutations in two siblings with short stature and neuro-cardio-facio-cutaneous features. BMJ Case Rep 2009; 2009
• 26 Niihori T, Aoki Y, Narumi Y , et al. Germline KRAS and BRAF mutations in cardio-facio-cutaneous syndrome. Nat Genet 2006; 38 (3) 294-296
• 27 Groesser L, Herschberger E, Ruetten A , et al. Postzygotic HRAS and KRAS mutations cause nevus sebaceous and Schimmelpenning syndrome. Nat Genet 2012; 44 (7) 783-787
• 28 Siddiqui MA, Siddiqui S, Zaman N, Ahmad I, Ullah E. Neurocutaneous melanosis: Review of a rare non-familial neuroectodermal dysplasia with newer association of cerebellopontine angle cistern lipoma. Neuroradiol J 2015; 28 (2) 222-226
• 29 Kinsler VA, Thomas AC, Ishida M , et al. Multiple congenital melanocytic nevi and neurocutaneous melanosis are caused by postzygotic mutations in codon 61 of NRAS. J Invest Dermatol 2013; 133 (9) 2229-2236
• 30 Salgado CM, Basu D, Nikiforova M , et al. BRAF mutations are also associated with neurocutaneous melanocytosis and large/giant congenital melanocytic nevi. Pediatr Dev Pathol 2015; 18 (1) 1-9
• 31 Rivière J-B, Mirzaa GM, O'Roak BJ , et al; Finding of Rare Disease Genes (FORGE) Canada Consortium. De novo germline and postzygotic mutations in AKT3, PIK3R2 and PIK3CA cause a spectrum of related megalencephaly syndromes. Nat Genet 2012; 44 (8) 934-940
• 32 Keppler-Noreuil KM, Rios JJ, Parker VER , et al. PIK3CA-related overgrowth spectrum (PROS): diagnostic and testing eligibility criteria, differential diagnosis, and evaluation. Am J Med Genet A 2015; 167A (2) 287-295
• 33 Loconte DC, Grossi V, Bozzao C , et al. Molecular and functional characterization of three different postzygotic mutations in PIK3CA-related overgrowth spectrum (PROS) patients: effects on PI3K/AKT/mTOR signaling and sensitivity to PIK3 inhibitors. PLoS ONE 2015; 10 (4) e0123092
• 34 Mirzaa GM, Conway RL, Gripp KW , et al. Megalencephaly-capillary malformation (MCAP) and megalencephaly-polydactyly-polymicrogyria-hydrocephalus (MPPH) syndromes: two closely related disorders of brain overgrowth and abnormal brain and body morphogenesis. Am J Med Genet A 2012; 158A (2) 269-291
• 35 Fu X, Osborne CK, Schiff R. Biology and therapeutic potential of PI3K signaling in ER+/HER2-negative breast cancer. Breast 2013; 22 (Suppl. 02) S12-S18
• 36 Alomari AI. Characterization of a distinct syndrome that associates complex truncal overgrowth, vascular, and acral anomalies: a descriptive study of 18 cases of CLOVES syndrome. Clin Dysmorphol 2009; 18 (1) 1-7
• 37 Gucev ZS, Tasic V, Jancevska A , et al. CLOVE syndrome (congenital lipomatous overgrowth, vascular malformations, and epidermal nevi): CNS malformations and seizures may be a component of this disorder. Am J Med Genet A 2008; 146A: 2688-2690
• 38 Milella M, Falcone I, Conciatori F , et al. PTEN: multiple functions in human malignant tumors. Front Oncol 2015; 5: 24
• 39 Pilarski R, Eng C. Will the real Cowden syndrome please stand up (again)? Expanding mutational and clinical spectra of the PTEN hamartoma tumour syndrome. J Med Genet 2004; 41 (5) 323-326
• 40 Bubien V, Bonnet F, Brouste V , et al; French Cowden Disease Network. High cumulative risks of cancer in patients with PTEN hamartoma tumour syndrome. J Med Genet 2013; 50 (4) 255-263
• 41 Goffin A, Hoefsloot LH, Bosgoed E, Swillen A, Fryns JP. PTEN mutation in a family with Cowden syndrome and autism. Am J Med Genet 2001; 105 (6) 521-524
• 42 Tan W-H, Baris HN, Burrows PE , et al. The spectrum of vascular anomalies in patients with PTEN mutations: implications for diagnosis and management. J Med Genet 2007; 44 (9) 594-602
• 43 Caux F, Plauchu H, Chibon F , et al. Segmental overgrowth, lipomatosis, arteriovenous malformation and epidermal nevus (SOLAMEN) syndrome is related to mosaic PTEN nullizygosity. Eur J Hum Genet 2007; 15 (7) 767-773
• 44 Happle R. Superimposed segmental manifestation of both rare and common cutaneous disorders: a new paradigm. Actas Dermosifiliogr 2009; 100 (Suppl. 01) 77-85
• 45 Huang J, Manning BD. The TSC1-TSC2 complex: a molecular switchboard controlling cell growth. Biochem J 2008; 412 (2) 179-190
• 46 Lindhurst MJ, Sapp JC, Teer JK , et al. A mosaic activating mutation in AKT1 associated with the Proteus syndrome. N Engl J Med 2011; 365 (7) 611-619
• 47 Tibbles JA, Cohen Jr MM. The Proteus syndrome: the Elephant Man diagnosed. Br Med J (Clin Res Ed) 1986; 293 (6548) 683-685
• 48 Hussain K, Challis B, Rocha N , et al. An activating mutation of AKT2 and human hypoglycemia. Science 2011; 334 (6055) 474
• 49 Cohen Jr MM. Proteus syndrome review: molecular, clinical, and pathologic features. Clin Genet 2014; 85 (2) 111-119
• 50 Beachkofsky TM, Sapp JC, Biesecker LG, Darling TN. Progressive overgrowth of the cerebriform connective tissue nevus in patients with Proteus syndrome. J Am Acad Dermatol 2010; 63 (5) 799-804
• 51 Biesecker L. The challenges of Proteus syndrome: diagnosis and management. Eur J Hum Genet 2006; 14 (11) 1151-1157
• 52 Jacks SK, Witman PM. Tuberous sclerosis complex: an update for dermatologists. Pediatr Dermatol 2015;
• 53 Navarre P, Poitras B. Lymphoedema in tuberous sclerosis: case report and review of the literature. J Pediatr Orthop 2014; 34 (6) e27-e32
• 54 Wong H, Hadi M, Khoury T, Geary D, Rubin B, Filler G. Management of severe hypertension in a child with tuberous sclerosis-related major vascular abnormalities. J Hypertens 2006; 24 (3) 597-599
• 55 Sampson JR. Therapeutic targeting of mTOR in tuberous sclerosis. Biochem Soc Trans 2009; 37 (Pt 1) 259-264
• 56 Chapman PB, Hauschild A, Robert C , et al; BRIM-3 Study Group. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med 2011; 364 (26) 2507-2516
• 57 Lopez S, Schwab CL, Cocco E , et al. Taselisib, a selective inhibitor of PIK3CA, is highly effective on PIK3CA-mutated and HER2/neu amplified uterine serous carcinoma in vitro and in vivo. Gynecol Oncol 2014; 135 (2) 312-317
• 58 Sadowski K, Kotulska-Jóźwiak K, Jóźwiak S. Role of mTOR inhibitors in epilepsy treatment. Pharmacol Rep 2015; 67 (3) 636-646