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  • Print publication year: 2004
  • Online publication date: July 2009

2 - Genetics of neurocutaneous disorders

    • By Kit-Sing Au, Division of Medical Genetics, Department of Pediatrics, The University of Texas Medical School at Houston, Houston, Texas, USA, Hope Northrup, Division of Medical Genetics, Department of Pediatrics, The University of Texas Medical School at Houston, Houston, Texas, USA
  • Edited by E. Steve Roach, Wake Forest University, North Carolina, Van S. Miller, University of Texas Southwestern Medical Center, Dallas
  • Publisher: Cambridge University Press
  • DOI:
  • pp 6-23



Neurocutaneous disorders in humans affect both the nervous system and the skin. Developmentally, both the skin and nervous system arise from embryonic ectoderm. There are more than 40 such disorders described in this text, with the majority displaying Mendelian inheritance. Mendelian inheritance refers to so-called ‘single gene’ conditions; conditions that have a specific clinical picture (phenotype) based on mutation of one gene. All the many facets of a disease and the multitude of differences between one affected person and another cannot be attributed entirely to the action of a single gene. There are modifier genes that influence phenotype as well as environmental conditions. ‘Single gene’ conditions are sometimes genetically heterogeneous; mutations in different genes can result in similar (often indistinguishable) phenotypes. Many of the neurocutaneous diseases exhibit variable phenotypes due to different mutations in a single gene (e.g. the proto-oncogene RET in multiple endocrine neoplasia type 2B (MEN2B), or the ATP-binding cassette C6 gene (ABCC6) in Pseudoxanthoma elasticum) while others have very similar phenotypes that result from mutations at different genetic loci (e.g. the Osler–Rendu–Weber syndromes and tuberous sclerosis complex). Disease-causing mutations in the causative genes have been identified for many of the neurocutaneous disorders during the past 15 years as a result of the rapid technologic advances in gene hunting. This chapter is devoted to discussing the hereditary patterns and causative genes.

Inheritance patterns

The hereditary influence on the traits of living organisms mainly resides in the chemical information of the nucleic acids (genes) of the organism.

Bassi, M. T., Ramesar, R. S., Caciotti, B. et al. (1999). X-linked late-onset sensorineural deafness caused by a deletion involving OA1 and a novel gene containing WD-40 repeats. American Journal of Human Genetics, 64(6): 1604–1616
Bauer, E. A., Santa-Cruz, D. J. & Eisen, A. Z. (1981). Lipoid proteinosis: in vivo and in vitro evidence for a lysosomal storage disease. Journal Investigative Dermatology, 76: 119–125
Bergen, A. A. B., Plomp, A. S., Schuurman, E. J. et al. (2000). Mutations in ABCC6 cause pseudoxanthoma elasticum. Nature Genetics, 25: 228–231
Bernstein, H. S., Bishop, D. F., Astrin, K. H. et al. (1989). Fabry disease: six gene rearrangements and an exonic point mutation in the alpha-galactosidase gene. Journal Clinical Investigation, 83: 1390–1399
Beutler, E., Kuhl, W., Trinidad, F., Teplitz, R. L. & Nadler, H. (1971). Beta-glucosidase activity in fibroblasts from homozygotes and heterozygotes for Gaucher's disease. American Journal of Human Genetics, 23: 62–66
Bianco, P., Riminucci, M., Majolagbe, A. et al. (2000). Mutations of the GNAS1 gene, stromal cell dysfunction, and osteomalacic changes in McCune-Albright fibrous dysplasia of bone. Journal of Bone Mineral Research, 15: 120–128
Boissy, R. E., Zhao, H., Oetting, W. S. et al. (1996). Mutation in and lack of expression of tyrosinase-related protein-1 (TRP-1) in melanocytes from an individual with brown oculocutaneous albinism: a new subtype of albinism classified as ‘OCA3.’American Journal of Human Genetics, 58: 1145–1156
Bomont, P., Cavalier, L., Blondeau, F. et al. (2000). The gene encoding gigaxonin, a new member of the cytoskeletal BTB/kelch repeat family, is mutated in giant axonal neuropathy. Nature Genetics, 26(3): 370–374
Bongarzone, I., Vigano, E., Alberti, L. et al. (1998). Full activation of MEN2B mutant RET by an additional MEN2A mutation or by ligand GDNF stimulation. Oncogene, 16: 2295–2301
Braverman, N., Steel, G., Obie, C. et al. (1997). Human PEX7 encodes the peroxisomal PTS2 receptor and is responsible for rhizomelic chondrodysplasia punctata. Nature Genetics, 15: 369–376
Byers P. (2001). Disorders of Collagen Biosynthesis and Structure. In The Metabolic and Molecular Basis of Inherited Disease, 8th edn, eds. C. R. Scriver, A. L. Beaudet, W. S. Sly et al. pp. 5262–5271. New York, NY: McGraw-Hill
Cali, J. J., Hsieh, C.-L., Francke, U. & Russell, D. W. (1991). Mutations in the bile acid biosynthetic enzyme sterol 27-hydroxylase underlie cerebrotendinous xanthomatosis. Journal of Biological Chemistry, 266: 7779–7783
Cartier, N., Sarde, C-O., Douar, A-M., Mosser, J., Mandel, J-L. & Aubourg, P. (1993). Abnormal messenger RNA expression and a missense mutation in patients with X-linked adrenoleukodystrophy. Human Molecular Genetics, 2: 1949–1951
Chen, F., Kishida, T., Yao, M. et al. (1995). Germline mutations in the von Hippel-Lindau disease tumor suppressor gene: correlations with phenotype. Human Mutation, 5: 66–75
Cleaver, J. E., Thompson, L. H., Richardson, A. S. & States, J. C. (1999). A summary of mutations in the UV-sensitive disorders: xeroderma pigmentosum, Cockayne syndrome, and trichothiodystrophy. Human Mutation, 14(1): 9–22
Colige, A., Sieron, A. L., Li, S-W. et al. (1999). Human Ehlers-Danlos syndrome type VII C and bovine dermatosparaxis are caused by mutations in the procollagen I N-proteinase gene. American Journal of Human Genetics, 65: 308–317
Dean, J. C. S. & Cole, G. F. (1988). When is Proteus syndrome not Proteus syndrome? (Abstract), Clinical Genetics Society. Aberdeen, Scotland
Vet, E. C. J. M., Ijlst, L., Oostheim, W., Wanders, R. J. A. & Bosch, H. (1998). Alkyl-dihydroxyacetonephosphate synthase: fate in peroxisome biogenesis disorders and identification of the point mutation underlying a single enzyme deficiency. Journal of Biological Chemistry, 273: 10296–10301
DiLiberti, J. H. (1992). Correlation of skeletal muscle biopsy with phenotype in the familial macrocephaly syndromes. Journal of Medical Genetics, 29: 46–49
Dietz, H. C., Cutting, G. R., Pyeritz, R. E. et al. (1991). Marfan syndrome caused by a recurrent de novo missense mutation in the fibrillin gene. Nature, 352: 337–339
Eiberg, H., Mohr, J. & Nielsen, L. S. (1984). Linkage of plasma alpha-L-fucosidase (FUCA2) and the plasminogen (PLG) system. Clinical Genetics, 26: 23–29
European Chromosome 16 Tuberous Sclerosis Consortium. (1993). Identification and characterization of the tuberous sclerosis gene on chromosome 16. Cell, 75: 1305–1315
Flanigan, K. M., Crawford, T. O., Griffin, J. W. et al. (1998). Localization of the giant axonal neuropathy gene to chromosome 16q24. Annals of Neurology, 43: 143–148
Foo, D., Chang, Y. C. & Rossier, A. B. (1980). Spontaneous cervical epidural hemorrhage, anterior cord syndrome, and familial vascular malformation: case report. Neurology, 30: 308–311
Gallione, C. J., Pasyk, K. A., Boon, L. M. et al. (1995). A gene for familial venous malformations maps to chromosome 9p in a second large kindred. Journal of Medical Genetics, 32: 197–199
Gorski, J. L., Burright, E. N., Harnden, C. E., Stein, C. K., Glover, T. W. & Reyner, E. L. (1991). Localization of DNA sequences to a region within Xp11.21 between incontinentia pigmenti (IP1) X-chromosomal translocation breakpoints. American Journal of Human Genetics, 48: 53–64
Hamada, T., McLean, W. H. I., Ramsay, M. et al. (2002). Lipoid proteinosis maps to 1q21 and is caused by mutations in the extracellular matrix protein 1 gene (ECM1). Human Molecular Genetics, 11(7): 833–840
Happle, R. (1986). Cutaneous manifestation of lethal genes. Human Genetics, 72(3): 280
Henning, K. A., Li, L., Iyer, N. et al. (1995). The Cockayne syndrome group A gene encodes a WD repeat protein that interacts with CSB protein and a subunit of RNA polymerase II TFIIH. Cell, 82: 555–564
Hofstra, R. M. W., Landsvater, R. M., Ceccherini, I. et al. (1994). A mutation in the RET proto-oncogene associated with multiple endocrine neoplasia type 2B and sporadic medullary thyroid carcinoma. Nature, 367: 375–376
Hu, F. L., Gu, Z., Kozich, V., Kraus, J. P., Ramesh, V. & Shih, V. E. (1993). Molecular basis of cystathionine beta-synthase deficiency in pyridoxine responsive and nonresponsive homocystinuria. Human Molecular Genetics, 2: 1857–1860
Huang, S., Li, B., Gray, M. D., Oshima, J., Mian, I. S. & Campisi, J. (1998). The premature aging syndrome protein, WRN, is a 3-prime-5-prime exonuclease. Nature Genetics, 20: 114–115
Hwu, W. L., Suzuki, Y., Yang, X., Li, X., Chou, S. P., Narisawa, K. & Tsai, W. Y. (2000). Late-onset holocarboxylase synthetase deficiency with homologous R508W mutation. Journal Formos Medical Associates, 99(2): 174–177
Hyland, J., Ala-Kokko, L., Royce, P., Steinmann, B., Kivirikko, K. I. & Myllyla, R. (1992). A homozygous stop codon in the lysyl hydroxylase gene in two siblings with Ehlers–Danlos syndrome type VI. Nature Genetics, 2: 228–231
Igal, R. A. & Coleman, R. A. (1998). Neutral lipid storage disease: a genetic disorder with abnormalities in the regulation of phospholipid metabolism. Journal of Lipid Research, 39: 31–43
Johnson, D. W., Berg, J. N., Baldwin, M. A. et al. (1996a). Mutations in the activin receptor-like kinase 1 gene in hereditary haemorrhagic telangiectasia type 2. Nature Genetics, 13: 189–195
Johnson, R. L., Rothman, A. L., Xie, J. et al. (1996b). Human homolog of patched, a candidate gene for the basal cell nevus syndrome. Science, 272: 1668–1671
Kaler, S. G., Gallo, L. K., Proud, V. K. et al. (1994). Occipital horn syndrome and a mild Menkes phenotype associated with splice site mutations at the MNK locus. Nature Genetics, 8: 195–202
King, R. A., Hearing, V. J., Creel, D. J. & Oetting, W. S. (2001). Albinism. In The Metabolic and Molecular Basis of Inherited Disease, 8th Edn, eds. C. R. Scriver, A. L. Beaudet, W. S. Sly et al. pp. 5587–5627. New York, NY: McGraw-Hill
Kluwe, L. & Mautner, V.-F. (1998). Mosaicism in sporadic neurofibromatosis 2 patients. Human Molecular Genetics, 7: 2051–2055
Konig, A. & Happle, R. (1999). Linear lesions reflecting lyonization in women heterozygous for IFAP syndrome (ichthyosis follicularis with atrichia and photophobia). American Journal of Medical Genetics, 85: 365–368
Koprivica, V., Stone, D. L., Park, J. K. et al. (2000). Analysis and Classification of 304 Mutant Alleles in Patients with Type 1 and Type 3 Gaucher Disease. American Journal of Human Genetics, 66(6): 1777–1786
Krappmann, D., Hatada, E. N., Tegethoff, S. et al. (2000). The I {kappa}b kinase complex is tripartite and contains Ikk{gamma} but not IKAP as a regular component. Journal of Biological Chemistry, [epub ahead of print]
Kretz, K. A., Darby, J. K., Willems, P. J. & O'Brien, J. S. (1989). Characterization of EcoRI mutation in fucosidosis patients: a stop codon in the open reading frame. Journal of Molecular Neuroscience, 1: 177–180
Lamb, R. F., Roy, C., Diefenbach, T. J. et al. (2000). The TSC1 tumour suppressor hamartin regulates cell adhesion through ERM proteins and the GTPase Rho. National Cell Biology, 2(5): 281–287
Latif, F., Tory, K., Gnarra, J. et al. (1993). Identification of the von Hippel-Lindau disease tumor suppressor gene. Science, 260: 1317–1320
Lazaro, C., Ravella, A., Gaona, A., Volpini, V. & Estivill, X. (1994). Neurofibromatosis type 1 due to germ-line mosaicism in a clinically normal father. New England Journal of Medicine, 331(21): 1403–1407
Lefèvre, C., Jobard, F., Caux, F. et al. (2001). Mutations in CGI-58, the gene encoding a new protein of the esterase/lipase/thioesterase subfamily, in Chanarin–Dorfman syndrome. American Journal of Human Genetics, 69: 1002–1012
Saux, O., Urban, Z., Tschuch, C. et al. (2000). Mutations in a gene encoding an ABC transporter cause pseudoxanthoma elasticum. Nature Genetics, 25: 223–227
Liaw, D., Marsh, D. J., Li, J. et al. (1997). Germline mutations of the PTEN gene in Cowden disease, an inherited breast and thyroid cancer syndrome. Nature Genetics, 16: 64–67
McAllister, K. A., Grogg, K. M., Johnson, D. W. et al. (1994). Endoglin, a TGF-beta binding protein of endothelial cells, is the gene for hereditary haemorrhagic telangiectasia type 1. Nature Genetics, 8: 345–351
McCall, S., Ramzy, M. I., Cure, J. K. & Pai, G. S. (1992). Encephalocraniocutaneous lipomatosis and the Proteus syndrome: distinct entities with overlapping manifestations. American Journal of Medical Genetics, 43: 662–668
Mallery, D. L., Tanganelli, B., Colella, S. et al. (1998). Molecular analysis of mutations in the CSB (ERCC6) gene in patients with Cockayne syndrome. American Journal of Human Genetics, 62: 77–85
Manga, P., Kromberg, J. G. R., Box, N. F., Sturm, R. A., Jenkins, T. & Ramsay, M. (1997). Rufous oculocutaneous albinism in southern African blacks is caused by mutations in the TYRP1 gene. American Journal of Human Genetics, 61: 1095–1101
Masutani, C., Kusumoto, R., Yamada, A. et al. (1999). The XPV (xeroderma pigmentosum variant) gene encodes human DNA polymerase eta. Nature, 399: 700–704
Menasche, G., Pastural, E., Feldmann, J. et al. (2000). Mutations in RAB27A cause Griscelli syndrome associated with haemophagocytic syndrome. Nature Genetics, 25: 173–176
Motley, A. M., Hettema, E. H., Hogenhout, E. M. et al. (1997). Rhizomelic chondrodysplasia punctata is a peroxisomal protein targeting disease caused by a non-functional PTS2 receptor. Nature Genetics, 15: 377–380
Mukhopadhyay, D., Knebelmann, B., Cohen, H. T., Ananth, S. & Sukhatme, V. P. (1997). The von Hippel-Lindau tumor suppressor gene product interacts with Sp1 to repress vascular endothelial growth factor promoter activity. Molecular Cell Biology, 17: 5629–5639
Nagle, D. L., Karim, M. A., Woolf, E. A. et al. (1996). Identification and mutation analysis of the complete gene for Chediak-Higashi syndrome. Nature Genetics, 14(3): 307–311
Natt, E., Kida, K., Odievre, M., Di Rocco, M. & Scherer, G. (1992). Point mutations in the tyrosine aminotransferase gene in tyrosinemia type II. Proceedings of the National Academy of Sciences, USA, 89(19): 9297–9301
Nazzaro, V., Ermacora, E., Santucci, B. & Caputo, R. (1990). Epidermolytic hyperkeratosis: generalized form in children from parents with systemized linear form. British Journal of Dermatology, 122: 417–422
Nelen, M. R., Padberg, G. W., Peeters, E. A. J. et al. (1996). Localization of the gene for Cowden disease to chromosome 10q22–23. Nature Genetics, 13: 114–116
Ofman, R., Hettema, E. H., Hogenhout, E. M., Caruso, U., Muijsers, A. O. & Wanders, R. J. A. (1998). Acyl-CoA: dihydroxyacetonephosphate acyltransferase: cloning of the human cDNA and resolution of the molecular basis in rhizomelic chondrodysplasia punctata type 2. Human Molecular Genetics, 7: 847–853
Paller, A. S., Syder, A. J., Chan, Y-M., Yu, Q-C., Hutton, E., Tadini, G. & Fuchs, E. (1994). Genetic and clinical mosaicism in a type of epidermal nevus. New England Journal of Medicine, 331: 1408–1415
Pastural, E., Barrat, F. J., Dufourcq-Lagelouse, R. et al. (1997). Griscelli disease maps to chromosome 15q21 and is associated with mutations in the myosin-Va gene. Nature Genetics, 16: 289–292. (Note: Erratum: Nature Genetics, 23: 373 only, 1999)
Pastural, E., Ersoy, F., Yalman, N. et al. (2000). Two genes are responsible for Griscelli syndrome at the same 15q21 locus. Genomics, 63: 299–306
Purdue, P. E., Zhang, J. W., Skoneczny, M. & Lararow, P. B. (1997). Rhizomelic chondrodysplasia punctata is caused by deficiency of human PEX7, a homologue of the yeast PTS2 receptor. Nature Genetics, 15: 381–384
Rantamaki, T., Kaitila, I., Syvanen, A. C., Lukka, M. & Peltonen, L. (1999). Recurrence of Marfan syndrome as a result of parental germ-line mosaicism for an FBN1 mutation. American Journal of Human Genetics. 64(4): 993–1001
Rinchik, E. M., Bultman, S. J., Horsthemke, B. et al. (1993). A gene for the mouse pink-eyed dilution locus and for human type II oculocutaneous albinism. Nature, 361: 72–76
Rizzo, R., Pavone, L., Micali, G., Nigro, F. & Cohen, M. M. Jr., (1993). Encephalocraniocutaneous lipomatosis, Proteus syndrome, and somatic mosaicism. American Journal of Medical Genetics, 47: 653–655
Rose, V. M., Au, K.-S., Pollom, G., Roach, E. S., Prashner, H. R. & Northrup, H. (1999). Germ-line mosaicism in tuberous sclerosis: how common? American Journal of Human Genetics, 64(4): 986–992
Rosenbloom, F. M., Kelley, W. N., Henderson, J. F. & Seegmiller, J. E. (1967). Lyon hypothesis and X-linked disease. (Letter), Lancet, II: 305–306
Rouleau, G. A., Merel, P., Lutchman, M. et al. (1993). Alteration in a new gene encoding a putative membrane-organizing protein causes neuro-fibromatosis type 2. Nature, 363: 515–521
Savitsky, K., Bar-Shira, A., Gilad, S. et al. (1995). A single ataxia telangiectasia gene with a product similar to PI-3 kinase. Science, 268: 1749–1753
Schiaffino, M. V., D'Addio, M., Alloni, A. et al. (1999). Ocular albinism: evidence for a defect in an intracellular signal transduction system. Nature Genetics, 23(1): 108–112
Sgambati, M. T., Stolle, C., Choyke, P. L. et al. (2000). Mosaicism in von Hippel-Lindau disease: lessons from kindreds with germline mutations identified in offspring with mosaic parents. American Journal of Human Genetics, 66(1): 84–91
Shiloh, Y., Litvak, G., Ziv, Y. et al. (1990). Genetic mapping of X-linked albinism-deafness syndrome (ADFN) to Xq26.3–q27.I. American Journal of Human Genetics, 47(1): 20–27
Slaugenhaupt, S. A., Blumenfeld, A., Gill, S. P. et al. (2001). Tissue-specific expression of a splicing mutation in the IKBKAP gene causes familial dysautonomia. American Journal of Human Genetics, 68(3): 598–605
Smyth, I., Narang, M. A., Evans, T. et al. (1999). Isolation and characterization of human Patched 2 (PTCH2), a putative tumour suppressor gene in basal cell carcinoma and medulloblastoma on chromosome 1p32. Human Molecular Genetics, 8: 291–297
Steichen-Gersdorf, E., Trawoger, R., Duba, H. C., Mayr, U., Felber, S. & Utermann, G. (1993). Hypomelanosis of Ito in a girl with a plexus papilloma and translocation (X;17). Human Genetics, 90: 611–613
Suzuki, Y., Aoki, Y., Ishida, Y. et al. (1994). Isolation and characterization of mutations in the human holocarboxylase synthetase cDNA. Nature Genetics, 8: 122–128
Sybert, V. P., Pagon, R. A., Donlan, M. & Bradley, C. M. (1990). Pigmentary abnormalities and mosaicism for chromosomal aberration: association with clinical features similar to hypomelanosis of Ito. Journal of Pediatrics, 116: 581–586
Takayama, K., Salazar, E. P., Broughton, B. C. et al. (1996). Defects in the DNA repair and transcription gene ERCC2(XPD) in trichothiodystrophy. American Journal of Human Genetics, 58: 263–270
The International Incontinentia Pigmenti Consortium. (2000). Genomic rearrangement in NEMO impairs NF-kappa-B activation and is a cause of incontinentia pigmenti. Nature, 405: 466–472
Tomita, Y., Takeda, A., Okinaga, S., Tagami, H. & Shibahara, S. (1989). Human oculocutaneous albinism caused by single base insertion in the tyrosinase gene. Biochemistry Biophysical Research Communications, 164: 990–996
Tsuji, S., Choudary, P. V., Martin, B. M. et al. (1987). A mutation in the human glucocerebrosidase gene in neuronopathic Gaucher's disease. New England Journal of Medicine, 316: 570–575
Turleau, C., Taillard, F., Doussau de Bazignan, M., Delephine, N., Desbois, J. C. & Grouchy, J. (1986). Hypomelanosis of Ito (incontinentia pigmenti achromians) and mosaicism for a microdeletion of 15q1. Human Genetics, 74: 185–187
Slegtenhorst, M., Hoogt, R., Hermans, C. et al. (1997). Identification of the tuberous sclerosis gene TSC1 on chromosome 9q34. Science, 277: 805–808
Verhoef, S., Bakker, L., Tempelaars, A. M. et al. (1999). High rate of mosaicism in tuberous sclerosis complex. American Journal of Human Genetics, 64(6): 1632–1637
Vikkula, M., Boon, L. M., Carraway, K. L., III et al. (1993). Vascular dysmorphogenesis caused by an activating mutation in the receptor tyrosine kinase TIE2. Cell, 87: 1181–1190
Walker, D. C., McCloskey, D. A., Simard, L. R. & McInnes, R. R. (1990). Molecular analysis of human argininosuccinate lyase: mutant characterization and alternative splicing of the coding region. Proc. National Academy of Science, 87: 9625–9629
Weeda, G., Eveno, E., Donker, I. et al. (1997), A mutation in the XPB/ERCC3 DNA repair transcription gene, associated with trichothiodystrophy. American Journal of Human Genetics, 60: 320–329
Weinstein, L. S., Shenker, A., Gejman, P. V., Merino, M. J., Friedman, E. & Spiegel, A. M. (1991). Activating mutations of the stimulatory G protein in the McCune–Albright syndrome. New England Journal of Medicine, 325: 1688–1695
Weiming, X., Yu, Q., Lizhi, L. et al. (1992). Molecular analysis of neurofibromatosis type 1 mutations. Human Mutation, 1: 474–477
Wienecke, R., Konig, A. & DeClue, J. E. (1995). Identification of tuberin, the tuberous sclerosis-2 product. Tuberin possesses specific Rap1GAP activity. Journal Biology Chemistry, 270(27): 16409–16414
Wilson, J. M. & Kelley, W. N. (1983). Molecular basis of hypoxanthine–guanine phosphoribosyltransferase deficiency in a patient with the Lesch–Nyhan syndrome. Journal of Clinical Investigators, 71: 1331–1335
Xiao, G. H., Shoarinejad, F., Jin, F., Golemis, E. A. & Yeung, R. S. (1997). The tuberous sclerosis 2 gene product, tuberin, functions as a Rab5 GTPase activating protein (GAP) in modulating endocytosis. Journal of Biological Chemistry, 272(10): 6097–6100
Yu, C-E., Oshima, J., Fu, Y-H. et al. (1996). Positional cloning of the Werner's syndrome gene. Science, 272: 258–262
Zhou, X. P., Marsh, D. J., Hampel, H., Mulliken, J. B., Gimm, O. & Eng, C. (2000). Germline and germline mosaic PTEN mutations associated with a Proteus-like syndrome of hemihypertrophy, lower limb asymmetry, arteriovenous malformations and lipomatosis. Human Molecular Genetics, 9(5): 765–768