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Somatic HRAS p.G12S Mutation Causes Woolly Hair and Epidermal Nevi

2013; Elsevier BV; Volume: 134; Issue: 4 Linguagem: Inglês

10.1038/jid.2013.430

1523-1747

Jonathan Levinsohn, Joyce Teng, Brittany G. Craiglow, Erin Loring, T. Burrow, Shrikant S. Mane, John D. Overton, Richard P. Lifton, Jennifer M. McNiff, Anne W. Lucky, Keith A. Choate,

Autoimmune Bullous Skin Diseases

Costello syndrome keratinocytic epidermal nevus loss of heterozygosity nevus sebaceus palmoplantar keratoderma single nucleotide variation woolly hair nevus Woolly hair nevus (WHN) is a mosaic disorder characterized by distinct patterns of tightly curled scalp hair, which can appear concurrently with epidermal nevi (EN) at other sites (Peteiro et al., 1989Peteiro C. Oliva N.P. Zulaica A. et al.Woolly-hair nevus: report of a case associated with a verrucous epidermal nevus in the same area.Pediatr Dermatol. 1989; 6: 188-190Crossref PubMed Scopus (15) Google Scholar; Venugopal et al., 2012Venugopal V. Karthikeyan S. Gnanaraj P. et al.Woolly hair nevus: a rare entity.Int J Trichology. 2012; 4: 42-43Crossref PubMed Scopus (14) Google Scholar). Woolly hair is also found in congenital disorders resulting from mutations affecting diverse cellular components, including intermediate filament, adherens junction, and signal–transduction proteins (Harel and Christiano, 2012Harel S. Christiano A.M. Genetics of structural hair disorders.J Invest Dermatol. 2012; 132: E22-E26Abstract Full Text Full Text PDF PubMed Scopus (13) Google Scholar). Embryonic somatic mutation causes mosaic disorders, which appear in patterns of ectodermal progenitor dorsovental migration. Somatic mutations causing mosaic disorders, including Proteus syndrome (Lindhurst et al., 2011Lindhurst M.J. Sapp J.C. Teer J.K. et al.A mosaic activating mutation in AKT1 associated with the Proteus syndrome.N Engl J Med. 2011; 365: 611-619Crossref PubMed Scopus (629) Google Scholar), port-wine stains (Shirley et al., 2013Shirley M.D. Tang H. Gallione C.J. et al.Sturge-Weber syndrome and port-wine stains caused by somatic mutation in GNAQ.N Engl J Med. 2013; 368: 1971-1979Crossref PubMed Scopus (644) Google Scholar), and EN (Levinsohn et al., 2013Levinsohn J.L. Tian L.C. Boyden L.M. et al.Whole-exome sequencing reveals somatic mutations in HRAS and KRAS, which cause nevus sebaceus.J Invest Dermatol. 2013; 133: 827-830Abstract Full Text Full Text PDF PubMed Scopus (69) Google Scholar; Sun et al., 2013Sun B.K. Saggini A. Sarin K.Y. et al.Mosaic activating RAS mutations in nevus sebaceus and nevus sebaceus syndrome.J Invest Dermatol. 2013; 133: 824-827Abstract Full Text Full Text PDF PubMed Scopus (48) Google Scholar), have been found using exome sequencing. Recognizing that exome sequencing would permit identification of mutations causing WHN, we ascertained two cases. Our first (WHN100; Figure 1a–d) case was a 10-year-old girl without history of developmental delay who had regions of slightly curly hair over her occipital scalp from infancy, which progressively curled with no scalp surface change and lie alongside the areas of straight hair. She had hyperpigmented patches on her neck, trunk, and arms, with more keratotic lesions on her distal extremities, and acanthosis nigricans in both axillae. There was linear palmoplantar keratoderma (PPK) and hyperkeratosis over most metacarpophalangeal and some proximal interphalangeal joints. Given concurrent PPK and woolly hair, clinical concern for Naxos or Carvajal syndromes led to regular cardiology evaluations that found no abnormalities. Our second case (WHN101; Figure 1e–h) was a 6-year-old girl whose hair developed at age 1 and consisted of a mixture of poker-straight hair and curly, thin hair. In infancy, she developed linear dyspigmentation on the right arm and trunk, which became more raised and scaly on the distal extremities over time. She had normal development, with no cardiac or ophthalmic abnormalities found on routine physical examination, cardiac magnetic resonance imaging, and serial electrocardiograms. Clinical suspicion of mosaic Naxos or Caravajal syndrome motivated clinical sequencing of DSP, DSC1, DSG1, JUP, PKP2, and TMEM43; no mutations were found. To determine the genetic basis of WHN, we performed paired whole-exome sequencing of DNA isolated from affected tissue and blood in both cases (Supplementary Table S1 online). Data were analyzed to identify somatic single nucleotide variants (SNVs), deletions, and insertions (Supplementary Methods online). A somatic heterozygous HRAS c.34G>A, p.G12S substitution was found in each (Figure 2a). There was no evidence of loss of heterozygosity (LOH) (Supplementary Figure S1 online) or secondary mutation somatic mutation, suggesting that HRAS mutation alone is sufficient to cause WHN. Sanger sequencing confirmed mutation presence in affected tissue (Figure 2b and c). To determine whether this mutation causes woolly hair, we prepared DNA from hair bulbs of straight and curly hair obtained from affected individual WHN101, finding the HRAS p.G12S mutation in curly hair only (Figure 2d and Supplementary Figure S2 online). Download .pdf (10.49 MB) Help with pdf files Supplementary Information Consistent with somatic mosaicism in an epidermal progenitor, prior cases of WHN have been reported with concurrent keratinocytic epidermal nevi (KEN). KEN result from somatic mutations in HRAS, KRAS, PIK3CA, FGFR3, and NRAS (Hafner et al., 2012Hafner C. Toll A. Gantner S. et al.Keratinocytic epidermal nevi are associated with mosaic RAS mutations.J Med Genet. 2012; 49: 249-253Crossref PubMed Scopus (75) Google Scholar) including the HRAS p.G12S mutation found in WHN (Hafner et al., 2011Hafner C. Toll A. Real F.X. HRAS mutation mosaicism causing urothelial cancer and epidermal nevus.N Engl J Med. 2011; 365: 1940-1942Crossref PubMed Scopus (34) Google Scholar). Furthermore, Costello syndrome (CS), in which patients present with developmental delay, high birth weight, feeding difficulties, failure to thrive, cardiac anomalies, and curly hair, results from germline heterozygous HRAS mutations, including p.G12S (Gripp and Lin, 2012Gripp K.W. Lin A.E. Costello syndrome: a Ras/mitogen activated protein kinase pathway syndrome (rasopathy) resulting from HRAS germline mutations.Genet Med. 2012; 14: 285-292Abstract Full Text Full Text PDF PubMed Scopus (113) Google Scholar; Siegel et al., 2012Siegel D.H. Mann J.A. Krol A.L. et al.Dermatological phenotype in Costello syndrome: consequences of Ras dysregulation in development.Br J Dermatol. 2012; 166: 601-607Crossref PubMed Scopus (60) Google Scholar). The timing of somatic mutation during embryonic development determines extent of cutaneous involvement and presence of other systemic abnormalities (Moss et al., 1993Moss C. Larkins S. Stacey M. et al.Epidermal mosaicism and Blaschko's lines.J Med Genet. 1993; 30: 752-755Crossref PubMed Scopus (81) Google Scholar). Notably, somatic activating HRAS mutations are found in most cases of nevus sebaceus (NS), a mosaic lesion which typically appears on the scalp and features alopecia, papillomatosis, and marked sebaceous hyperplasia (Groesser et al., 2012Groesser L. Herschberger E. Ruetten A. et al.Postzygotic HRAS and KRAS mutations cause nevus sebaceous and Schimmelpenning syndrome.Nat Genet. 2012; 44: 783-787Crossref PubMed Scopus (212) Google Scholar; Levinsohn et al., 2013Levinsohn J.L. Tian L.C. Boyden L.M. et al.Whole-exome sequencing reveals somatic mutations in HRAS and KRAS, which cause nevus sebaceus.J Invest Dermatol. 2013; 133: 827-830Abstract Full Text Full Text PDF PubMed Scopus (69) Google Scholar; Sun et al., 2013Sun B.K. Saggini A. Sarin K.Y. et al.Mosaic activating RAS mutations in nevus sebaceus and nevus sebaceus syndrome.J Invest Dermatol. 2013; 133: 824-827Abstract Full Text Full Text PDF PubMed Scopus (48) Google Scholar). These features contrast with those of WHN in which hair is present but curly, and sebaceous hyperplasia is absent. Given that WHN and NS are both caused by somatic HRAS mutations, we hypothesize that their phenotypic divergence may derive from relative potency of the mutant allele with respect to mitogen-activated protein kinase activation. HRAS mutations in WHN and NS fall within the finger loop of HRAS, replacing glycine residues with larger amino acids that prevent guanosine triphosphate hydrolysis (Malumbres and Barbacid, 2003Malumbres M. Barbacid M. RAS oncogenes: the first 30 years.Nat Rev Cancer. 2003; 3: 459-465Crossref PubMed Scopus (1427) Google Scholar). Though comparison of the WHN p.G12S mutation and the common NS p.G13R mutation has not been performed, HRAS codon 12 serine substitutions have been shown to be less activating than arginine, aspartic acid, or valine substitutions (Fasano et al., 1984Fasano O. Aldrich T. Tamanoi F. et al.Analysis of the transforming potential of the human H-ras gene by random mutagenesis.Proc Natl Acad Sci USA. 1984; 81: 4008-4012Crossref PubMed Scopus (202) Google Scholar). To evaluate the frequency of HRAS mutation in NS, we screened 116 archival scalp NS lesions for HRAS and KRAS mutations. We found 88 HRAS and 9 KRAS mutations. HRAS p.G13R was present in 85 NS and p.G12S was not found (Supplementary Table S2 online). In prior reports, 64 additional samples were screened, and HRAS p.G12S mutations were not found (Levinsohn et al., 2013Levinsohn J.L. Tian L.C. Boyden L.M. et al.Whole-exome sequencing reveals somatic mutations in HRAS and KRAS, which cause nevus sebaceus.J Invest Dermatol. 2013; 133: 827-830Abstract Full Text Full Text PDF PubMed Scopus (69) Google Scholar; Sun et al., 2013Sun B.K. Saggini A. Sarin K.Y. et al.Mosaic activating RAS mutations in nevus sebaceus and nevus sebaceus syndrome.J Invest Dermatol. 2013; 133: 824-827Abstract Full Text Full Text PDF PubMed Scopus (48) Google Scholar). In one report, three specimens with HRAS p.G12S mutations were identified; in two there was a concurrent HRAS p.G13R mutation, and in one, the lesion was on the ear, a site at which it could be difficult to distinguish EN and NS (Groesser et al., 2012Groesser L. Herschberger E. Ruetten A. et al.Postzygotic HRAS and KRAS mutations cause nevus sebaceous and Schimmelpenning syndrome.Nat Genet. 2012; 44: 783-787Crossref PubMed Scopus (212) Google Scholar). These data combined with evidence from CS suggest that more strongly activating RAS mutations may cause the alopecia and sebaceous hyperplasia found in NS, and the more mildly activating p.G12S mutation causes woolly hair phenotypes. In summary, we find somatic HRAS c.34G>A, p.G12S mutation in affected tissue from two cases with mosaic woolly hair and EN. Consistent with reports of WHN and in KEN, the identified p.G12S mutation causes an EN phenotype on the body, but the finding of curly hair on the scalp suggests that WHN represents a mosaic RASopathy with phenotype determined by location, either due to distinct epidermal progenitor types or site-specific mesenchymal interactions. We hypothesize that in contrast to strongly activating RAS mutations found in NS, which drive hair follicle progenitors toward sebocyte differentiation, the more weakly activating mutation found in WHN permits an intermediate phenotype with abnormal curly hair growth but without sebaceous hyperplasia. Parental permission and child assent was obtained in writing for each of our cases and our study was approved by the Yale Human Investigational Committee and complies with the Declaration of Helsinki Principles. We thank Lynn Boyden and Young Lim for critical review of the manuscript, and Jing Zhou, Young Lim, Li Tian, Carol Nelson-Williams, Gerald Goh, and Samir Zaidi for technical assistance. This work was supported by a Doris Duke Charitable Foundation Clinical Scientist Development Award to KAC, and by the Yale Center for Mendelian Genomics (NIH U54 HG006504). JLL is a recipient of a Clinical Research Mentorship Award from the Doris Duke Charitable Foundation and is supported by the Medical Scientist Training Program (NIH NIGMS GM007205) at Yale University. BGC is supported by a fellowship from the National Institutes of Health (NIH NIAMS T32AR007016) and by the Dermatology Foundation. Supplementary material is linked to the online version of the paper at http://www.nature.com/jid