- Email: [email protected]
Becker’s Nevus and Lethal Beta-Actin Mutations
COMMENTARY
Becker’s Nevus and Lethal Beta-Actin Mutations Rudolf Happle1 The etiology of Becker’s nevus and Becker’s nevus syndrome has been until now unknown. Cai et al. provide evidence that these disorders are caused by lethal mutations in ACTB, a gene coding for beta-actin. They hypothesize that these mutations may interfere with Hedgehog pathway signaling. Their findings have important implications for clinical genetics, and they open new aspects in hair research. Journal of Investigative Dermatology (2017) -, -e-. doi:10.1016/j.jid.2017.04.003
Becker’s nevus is a distinct type of organoid epidermal nevus that appears as a light brown patch with bizarre outlines resembling an archipelago. This androgen-dependent skin disorder shows increased hairiness in postpubertal males, but not in females. In Becker’s nevus syndrome, the cutaneous lesion is associated with other defects such as ipsilateral hypoplasia of breast and various skeletal and muscular anomalies (Cai et al., 2017). Beta-actin is a major cytoskeletal protein participating in many important cellular functions such as cell motility, vesicle and organelle movement, cell signaling, and the establishment and maintenance of cell junction and cell shape (Gunning et al., 2015). Beta-actin mRNA plays a pivotal role in cell migration during embryogenesis and differentiation. Cai et al. (2017) show convincingly that Becker’s nevus and Becker’s nevus syndrome are caused by postzygotic ACTB mutations. They identified such mutations in 14 of 23 Becker’s nevi. In three cases, the authors performed laser capture microdissection and found that the ACTB mutation was present exclusively in the arrector pili muscles, but the authors emphasize that these particular findings are preliminary because of the small number of cases. Lethal mutations that survive as mosaics
A peculiar aspect of the ACTB mutations p.R247C and p.R247S detected in 1
Becker’s nevus and Becker’s nevus syndrome is their lethality for the developing embryo. Hence, these phenotypes can now be added to the growing list of sporadic genodermatoses that reflect the action of lethal autosomal mutations being confirmed at the molecular level (Table 1). Comparison with disorders caused by nonlethal ACTB mutations
Several different nonlethal mutations of ACTB were identified in BaraitserWinter cerebrofrontofacial syndrome (Verloes et al., 2015). This is an autosomal dominant trait with craniofacial, visceral, and muscular involvement due to gain-of-function mutations in ACTB or ACTG1. Major features include hypertelorism, bilateral ptosis, ocular colobomata, metopic ridging, and trigonocephaly. The nose is wide, short, and upturned. Skeletal defects comprise short stature, dorsal kyphosis, anteverted shoulders, and limited joint movements with slightly flexed elbows and knees. Neurological anomalies occur in the form of motor delay, intellectual deficiency, and agyria or pachygyria. Other ACTB mutations were found to be associated with juvenile-onset dystonia (Procaccio et al., 2006), which is a severe autosomal dominant disorder of movement with involuntary muscle contractions, associated with neurosensory hearing loss, pronounced facial defects with bilateral ptosis and hypertelorism,
Department of Dermatology, Faculty of Medicine, University of Freiburg, Freiburg, Germany
Correspondence: Rudolf Happle, Department of Dermatology, University of Freiburg, Hauptstr. 7, 79104 Freiburg, Germany. E-mail: [email protected] ª 2017 The Author. Published by Elsevier, Inc. on behalf of the Society for Investigative Dermatology.
intellectual deficiency, and structural brain defects. Perhaps, however, juvenile-onset dystonia should merely be taken as a variant within the spectrum of Baraitser-Winter cerebrofrontofacial syndrome (Rivie`re et al., 2012b). Remarkably, all of these germline mutations produce musculoskeletal abnormalities that are reminiscent of those observed in Becker’s nevus syndrome. Possible interference with Hedgehog signaling
Cai et al. (2017) examined the molecular effects of the identified ACTB mutations p.R147C and p.R147S. They did not find any perturbations of F-actin cytoskeletal staining or of mitogenactivated protein kinase signaling, but a trend toward increased Hedgehog pathway signaling was noted in cells stimulated with a Smoothened agonist. Previous studies had indicated that there is a dynamic interaction between beta-actin and Hedgehog signaling (Stevenson and Theurkauf, 2000). Cai et al. (2017) hypothesize that the ACTB mutations p.R147 exert an intensifying effect on Hedgehog signaling, which may interfere with the development of hair follicles and arrector pili muscles. This concept may constitute a new aspect in hair research. Elimination of some historical errors
The literature on Becker’s nevus contains some historical errors. Hermann W. Siemens (1891e1969), the pioneering genodermatologist from Leiden (The Netherlands), firmly believed that this skin disorder should not be classified as a nevus because it was usually not visible at birth, which is why he called it “melanosis naeviformis” (Siemens, 1967). The scientific community, however, did not accept his view. The molecular findings presented by Cai et al. (2017) confirm that Siemens was wrong. Another error refers to lesional hypertrichosis that during many years was taken as a required diagnostic criterion of Becker’s nevus. In female patients such hairiness is usually absent, which is why Becker’s nevus was reported almost exclusively in males. Even at the end of the past century, the www.jidonline.org
1
COMMENTARY
Clinical Implications In Becker’s nevus and Becker’s nevus syndrome, the true sex ratio is 1:1. Molecular findings provide proof that the hypothesis of paradominant inheritance was incorrect. In these traits, the genetic risk of recurrence is practically zero.
male:female ratio of isolated Becker’s nevus was said to be 6:1 (MaessenVisch et al., 1997). In fact, the true sex ratio is most likely 1:1 (Happle and Koopman, 1997), and this view is supported by the molecular study of Cai et al. (2017). The following error was committed by myself (Happle, 1992). Because some familial cases of Becker’s nevus had been reported (Jain and Fisher, 1989; Panizzon and Schnyder 1988), I suggested that this skin disorder may represent a “paradominant” trait. Heterozygous individuals would be healthy. The disorder would only become manifest if loss of heterozygosity would occur at an early developmental stage, giving rise to a homozygous or hemizygous clone of cells. Meanwhile, however, I had retracted this bold hypothesis because from the molecular results obtained in other disorders such as nevus flammeus
or sebaceous nevus I concluded that, so far, no clinical example of paradominance could be proposed with any certitude (Happle, 2014). Ultimately, the study of Cai et al. (2017) provides molecular proof that the concept of paradominant inheritance of Becker’s nevus was incorrect. Some further questions
The enigma of how to explain the etiology of Becker’s nevus and Becker’s nevus syndrome has now been resolved. But as often happens in science, this solution of a problem generates many new questions. For example, how can we explain the familial aggregation of Becker’s nevi (Panizzon and Schnyder, 1988) and even Becker’s nevus syndrome (Maessen-Visch et al., 1997)? Do such cases simply reflect an arbitrary coincidence? If so, this would be an analogy to nevus sebaceus because this skin disorder
Disorder
OMIM No.1
McCune-Albright syndrome FGFR3 epidermal nevus syndrome Proteus syndrome Maffucci syndrome
174800 134934 176920 614569
CLOVES syndrome Megalencephaly-capillary malformation syndrome (Congenital livedo reticularismegalencephaly syndrome) Schimmelpenning syndrome2
612918 602501
Papular nevus spilus syndrome
163200 No entry
Sturge-Weber syndrome
185300
Oculoectodermal syndrome Becker nevus syndrome
600268 604919
1
Gene
Reference
GNAS1 FGFR3 AKT1 IDH1, IDH2 PIK3CA PIK3CA
Weinstein et al. (1991) Garcı´a-Vargas et al. (2008) Lindhurst et al. (2011) Pansuriya et al. (2011)
HRAS, KRAS HRAS
Groesser et al. (2012)
GNAQ, GNA11 KRAS ACTB
Kurek et al. (2012) Rivie`re et al. (2012a)
Groesser et al. (2013); Happle (2013) Shirley et al. (2013); Thomas et al. (2016) Peacock et al. (2015) Cai et al. (2017)
Online Mendelian Inheritance in Man, OMIM. McKusick-Nathans Institute for Genetic Medicine, Johns Hopkins University (Baltimore, MD) and National Center for Biotechnology Information, National Library of Medicine (Bethesda, MD), 2000. http://www.ncbi.nlm.nih.gov/omim/. 2 Including phacomatosis pigmentokeratotica. 3 This phenotype may also be taken as a clinical variant of Schimmelpenning syndrome.
2
CONFLICT OF INTEREST The author states no conflict of interest.
Table 1. Sporadic cutaneous phenotypes proven to be caused by lethal autosomal mutations surviving as mosaics
3
usually occurs sporadically and is caused by a lethal autosomal mutation, whereas, paradoxically, several cases of a familial aggregation have been reported (Fearfield and Bunker, 1998). On the other hand, congenital smooth muscle hamartoma is a nosologically related disorder that is sometimes associated with lesional hypertrichosis (Guarneri et al., 2015). Might this disorder likewise be caused by postzygotic mutations in beta-actin? In conclusion, the pioneering work of Cai et al. (2017) has opened new avenues for further research on the role of beta-actin in clinical genetics.
Journal of Investigative Dermatology (2017), Volume
-
REFERENCES Cai ED, Sun BK, Chiang A, Rogers A, Bernet L, Cheng B, et al. Postzygotic mutations in betaactin are associated with Becker’s nevus and Becker’s nevus syndrome. J Invest Dermatol 2017;137:XXXeXXX. Fearfield LA, Bunker CD. Familial naevus sebaceus of Jadassohn. Br J Dermatol 1998;139: 1119e20. Garcı´a-Vargas A, Hafner C, Pe´rez-Rodrı´guez AG, Rodrı´guez-Rojas LX, Gonza´lez-Esqueda P, Stoehr R, et al. An epidermal nevus syndrome with cerebral involvement caused by a mosaic FGFR3 mutation. Am J Med Genet A 2008;146A:2275e9. Groesser L, Herschberger E, Ruetten A, Ruivenkamp C, Lopriore E, Zutt M, et al. Postzygotic HRAS and KRAS mutations cause nevus sebaceous and Schimmelpenning syndrome. Nat Genet 2012;44:783e7. Groesser L, Herschberger E, Sagrera A, Shwayder T, Flux K, Ehmann L, et al. Phacomatosis pigmentokeratotica is caused by a postzygotic HRAS mutation in a multipotent progenitor cell. J Invest Dermatol 2013;133: 1998e2003. Guarneri C, Lentini M, Cannavo` SP, Happle R. A case of hypertrichotic smooth muscle hamartoma: is it an amelanotic Becker naevus? Clin Exp Dermatol 2015;40:577e9. Gunning PW, Ghoshdastider U, Whitaker S, Popp D, Robinson RC. The evolution of compositionally and functionally distinct acting filaments. J Cell Sci 2015;128:2009e19. Happle R. Paradominant inheritance: a possible explanation for Becker’s pigmented hairy nevus. Eur J Dermatol 1992;2:39e40. Happle R. Phacomatosis pigmentokeratotica is a “pseudodidymosis”. J Invest Dermatol 2013;133:1923e5. Happle R. Mosaicism in human skin: understanding nevi, nevoid skin disorders, and cutaneous neoplasia. Berlin: Springer; 2014. Happle R, Koopman RJ. Becker nevus syndrome. Am J Med Genet 1997;68:357e61. Jain HC, Fisher BK. Familial Becker’s nevus. Int J Dermatol 1989;28:263e4.
COMMENTARY Kurek KC, Luks VL, Ayturk UM, Alomari AI, Fishman SJ, Spencer SA, et al. Somatic mosaic activating mutations in PIK3CA cause CLOVES syndrome. Am J Hum Genet 2012;90: 1108e15. Lindhurst MJ, Sapp JC, Teer JK, Johnston JJ, Finn EM, Peters K, et al. A mosaic activating mutation in AKT1 associated with the Proteus syndrome. N Engl J Med 2011;365:611e9. Maessen-Visch MB, Hulsmans RF, Hulsmans FJ, Neumann HA. Melanosis naeviformis of Becker and scoliosis: a coincidence? Acta Derm Venereol 1997;77:135e6. Panizzon R, Schnyder UW. Familial Becker’s nevus. Dermatologica 1988;176:275e6. Pansuriya TC, van Eijk R, d’Adamo P, van Ruler MA, Kuijjer ML, Oosting J, et al. Somatic mosaic IDH1 and IDH2 mutations are associated with enchondroma and spindle cell hemangioma in Ollier disease and Maffucci syndrome. Nat Genet 2011;43: 1256e61. Peacock JD, Dykema KJ, Toriello HV, Mooney MR, Scholten DJ II, Winn ME, et al.
Oculoectodermal syndrome is a mosaic RASopathy associated with KRAS alterations. Am J Med Genet A 2015;167:1429e35. Procaccio V, Salazar G, Ono S, Styers ML, Gearing M, Davila A, et al. A mutation of betaactin that alters depolymerization dynamics is associated with autosomal dominant developmental malformations, deafness, and dystonia. Am J Hum Genet 2006;78:947e60.
Siemens HW. Die naevusa¨ hnliche Melanose (Melanosis naeviformis, alias Naevus pigmentosus tardus) [The nevus-like melanosis (melanosis naeviformis, alias nevus pigmentosus tardus]. Hautarzt 1967;18: 299e303. Stevenson VA, Theurkauf WE. Actin cytoskeleton: putting a CAP on actin polymerization. Curr Biol 2000;10:R695e7.
Rivie`re JB, Mirzaa GM, O’Roak BJ, Beddaoui M, Alcantara D, Conway RL, et al. De novo germline and postzygotic mutations in AKT3, PIK3R2 and PIK3CA cause a spectrum of related megalencephaly syndromes. Nat Genet 2012a;44:934e40.
Thomas AC, Zeng Z, Rivie`re JB, O’Shaughnessy R, Al-Olabi L, St-Onge J, et al. Mosaic activating mutations in GNA11 and GNAQ are associated with phakomatosis pigmentovascularis and extensive dermal melanocytosis. J Invest Dermatol 2016;136:770e8.
Rivie`re JB, van Bon BWM, Hoischen A, Kholmanskikh S, O’Roak BJ, Gilissen C, et al. De novo mutations in the actin genes ACTB and ACTG1 cause Baraitser-Winter syndrome. Nature Genet 2012b;44:440e4.
Verloes A, Di Donato N, Masliah-Planchon J, Jongmans M, Abdul-Raman OA, Albrecht B, et al. Baraitser-Winter cerebrofrontofacial syndrome: delineation of the spectrum in 42 cases. Eur J Hum Genet 2015;23:292e301.
Shirley MD, Tang H, Gallione CJ, Baugher JD, Frelin LP, Cohen B, et al. Sturge-Weber syndrome and port-wine stains caused by somatic mutation in GNAQ. N Engl J Med 2013;368: 1971e9.
Weinstein LS, Shenker A, Gejman PV, Merino MJ, Friedman E, Spiegel AM. Activating mutations of the stimulatory G protein in the McCuneAlbright syndrome. N Engl J Med 1991;325: 1688e95.
www.jidonline.org
3
Becker’s Nevus and Lethal Beta-Actin Mutations Rudolf Happle1 The etiology of Becker’s nevus and Becker’s nevus syndrome has been until now unknown. Cai et al. provide evidence that these disorders are caused by lethal mutations in ACTB, a gene coding for beta-actin. They hypothesize that these mutations may interfere with Hedgehog pathway signaling. Their findings have important implications for clinical genetics, and they open new aspects in hair research. Journal of Investigative Dermatology (2017) -, -e-. doi:10.1016/j.jid.2017.04.003
Becker’s nevus is a distinct type of organoid epidermal nevus that appears as a light brown patch with bizarre outlines resembling an archipelago. This androgen-dependent skin disorder shows increased hairiness in postpubertal males, but not in females. In Becker’s nevus syndrome, the cutaneous lesion is associated with other defects such as ipsilateral hypoplasia of breast and various skeletal and muscular anomalies (Cai et al., 2017). Beta-actin is a major cytoskeletal protein participating in many important cellular functions such as cell motility, vesicle and organelle movement, cell signaling, and the establishment and maintenance of cell junction and cell shape (Gunning et al., 2015). Beta-actin mRNA plays a pivotal role in cell migration during embryogenesis and differentiation. Cai et al. (2017) show convincingly that Becker’s nevus and Becker’s nevus syndrome are caused by postzygotic ACTB mutations. They identified such mutations in 14 of 23 Becker’s nevi. In three cases, the authors performed laser capture microdissection and found that the ACTB mutation was present exclusively in the arrector pili muscles, but the authors emphasize that these particular findings are preliminary because of the small number of cases. Lethal mutations that survive as mosaics
A peculiar aspect of the ACTB mutations p.R247C and p.R247S detected in 1
Becker’s nevus and Becker’s nevus syndrome is their lethality for the developing embryo. Hence, these phenotypes can now be added to the growing list of sporadic genodermatoses that reflect the action of lethal autosomal mutations being confirmed at the molecular level (Table 1). Comparison with disorders caused by nonlethal ACTB mutations
Several different nonlethal mutations of ACTB were identified in BaraitserWinter cerebrofrontofacial syndrome (Verloes et al., 2015). This is an autosomal dominant trait with craniofacial, visceral, and muscular involvement due to gain-of-function mutations in ACTB or ACTG1. Major features include hypertelorism, bilateral ptosis, ocular colobomata, metopic ridging, and trigonocephaly. The nose is wide, short, and upturned. Skeletal defects comprise short stature, dorsal kyphosis, anteverted shoulders, and limited joint movements with slightly flexed elbows and knees. Neurological anomalies occur in the form of motor delay, intellectual deficiency, and agyria or pachygyria. Other ACTB mutations were found to be associated with juvenile-onset dystonia (Procaccio et al., 2006), which is a severe autosomal dominant disorder of movement with involuntary muscle contractions, associated with neurosensory hearing loss, pronounced facial defects with bilateral ptosis and hypertelorism,
Department of Dermatology, Faculty of Medicine, University of Freiburg, Freiburg, Germany
Correspondence: Rudolf Happle, Department of Dermatology, University of Freiburg, Hauptstr. 7, 79104 Freiburg, Germany. E-mail: [email protected] ª 2017 The Author. Published by Elsevier, Inc. on behalf of the Society for Investigative Dermatology.
intellectual deficiency, and structural brain defects. Perhaps, however, juvenile-onset dystonia should merely be taken as a variant within the spectrum of Baraitser-Winter cerebrofrontofacial syndrome (Rivie`re et al., 2012b). Remarkably, all of these germline mutations produce musculoskeletal abnormalities that are reminiscent of those observed in Becker’s nevus syndrome. Possible interference with Hedgehog signaling
Cai et al. (2017) examined the molecular effects of the identified ACTB mutations p.R147C and p.R147S. They did not find any perturbations of F-actin cytoskeletal staining or of mitogenactivated protein kinase signaling, but a trend toward increased Hedgehog pathway signaling was noted in cells stimulated with a Smoothened agonist. Previous studies had indicated that there is a dynamic interaction between beta-actin and Hedgehog signaling (Stevenson and Theurkauf, 2000). Cai et al. (2017) hypothesize that the ACTB mutations p.R147 exert an intensifying effect on Hedgehog signaling, which may interfere with the development of hair follicles and arrector pili muscles. This concept may constitute a new aspect in hair research. Elimination of some historical errors
The literature on Becker’s nevus contains some historical errors. Hermann W. Siemens (1891e1969), the pioneering genodermatologist from Leiden (The Netherlands), firmly believed that this skin disorder should not be classified as a nevus because it was usually not visible at birth, which is why he called it “melanosis naeviformis” (Siemens, 1967). The scientific community, however, did not accept his view. The molecular findings presented by Cai et al. (2017) confirm that Siemens was wrong. Another error refers to lesional hypertrichosis that during many years was taken as a required diagnostic criterion of Becker’s nevus. In female patients such hairiness is usually absent, which is why Becker’s nevus was reported almost exclusively in males. Even at the end of the past century, the www.jidonline.org
1
COMMENTARY
Clinical Implications In Becker’s nevus and Becker’s nevus syndrome, the true sex ratio is 1:1. Molecular findings provide proof that the hypothesis of paradominant inheritance was incorrect. In these traits, the genetic risk of recurrence is practically zero.
male:female ratio of isolated Becker’s nevus was said to be 6:1 (MaessenVisch et al., 1997). In fact, the true sex ratio is most likely 1:1 (Happle and Koopman, 1997), and this view is supported by the molecular study of Cai et al. (2017). The following error was committed by myself (Happle, 1992). Because some familial cases of Becker’s nevus had been reported (Jain and Fisher, 1989; Panizzon and Schnyder 1988), I suggested that this skin disorder may represent a “paradominant” trait. Heterozygous individuals would be healthy. The disorder would only become manifest if loss of heterozygosity would occur at an early developmental stage, giving rise to a homozygous or hemizygous clone of cells. Meanwhile, however, I had retracted this bold hypothesis because from the molecular results obtained in other disorders such as nevus flammeus
or sebaceous nevus I concluded that, so far, no clinical example of paradominance could be proposed with any certitude (Happle, 2014). Ultimately, the study of Cai et al. (2017) provides molecular proof that the concept of paradominant inheritance of Becker’s nevus was incorrect. Some further questions
The enigma of how to explain the etiology of Becker’s nevus and Becker’s nevus syndrome has now been resolved. But as often happens in science, this solution of a problem generates many new questions. For example, how can we explain the familial aggregation of Becker’s nevi (Panizzon and Schnyder, 1988) and even Becker’s nevus syndrome (Maessen-Visch et al., 1997)? Do such cases simply reflect an arbitrary coincidence? If so, this would be an analogy to nevus sebaceus because this skin disorder
Disorder
OMIM No.1
McCune-Albright syndrome FGFR3 epidermal nevus syndrome Proteus syndrome Maffucci syndrome
174800 134934 176920 614569
CLOVES syndrome Megalencephaly-capillary malformation syndrome (Congenital livedo reticularismegalencephaly syndrome) Schimmelpenning syndrome2
612918 602501
Papular nevus spilus syndrome
163200 No entry
Sturge-Weber syndrome
185300
Oculoectodermal syndrome Becker nevus syndrome
600268 604919
1
Gene
Reference
GNAS1 FGFR3 AKT1 IDH1, IDH2 PIK3CA PIK3CA
Weinstein et al. (1991) Garcı´a-Vargas et al. (2008) Lindhurst et al. (2011) Pansuriya et al. (2011)
HRAS, KRAS HRAS
Groesser et al. (2012)
GNAQ, GNA11 KRAS ACTB
Kurek et al. (2012) Rivie`re et al. (2012a)
Groesser et al. (2013); Happle (2013) Shirley et al. (2013); Thomas et al. (2016) Peacock et al. (2015) Cai et al. (2017)
Online Mendelian Inheritance in Man, OMIM. McKusick-Nathans Institute for Genetic Medicine, Johns Hopkins University (Baltimore, MD) and National Center for Biotechnology Information, National Library of Medicine (Bethesda, MD), 2000. http://www.ncbi.nlm.nih.gov/omim/. 2 Including phacomatosis pigmentokeratotica. 3 This phenotype may also be taken as a clinical variant of Schimmelpenning syndrome.
2
CONFLICT OF INTEREST The author states no conflict of interest.
Table 1. Sporadic cutaneous phenotypes proven to be caused by lethal autosomal mutations surviving as mosaics
3
usually occurs sporadically and is caused by a lethal autosomal mutation, whereas, paradoxically, several cases of a familial aggregation have been reported (Fearfield and Bunker, 1998). On the other hand, congenital smooth muscle hamartoma is a nosologically related disorder that is sometimes associated with lesional hypertrichosis (Guarneri et al., 2015). Might this disorder likewise be caused by postzygotic mutations in beta-actin? In conclusion, the pioneering work of Cai et al. (2017) has opened new avenues for further research on the role of beta-actin in clinical genetics.
Journal of Investigative Dermatology (2017), Volume
-
REFERENCES Cai ED, Sun BK, Chiang A, Rogers A, Bernet L, Cheng B, et al. Postzygotic mutations in betaactin are associated with Becker’s nevus and Becker’s nevus syndrome. J Invest Dermatol 2017;137:XXXeXXX. Fearfield LA, Bunker CD. Familial naevus sebaceus of Jadassohn. Br J Dermatol 1998;139: 1119e20. Garcı´a-Vargas A, Hafner C, Pe´rez-Rodrı´guez AG, Rodrı´guez-Rojas LX, Gonza´lez-Esqueda P, Stoehr R, et al. An epidermal nevus syndrome with cerebral involvement caused by a mosaic FGFR3 mutation. Am J Med Genet A 2008;146A:2275e9. Groesser L, Herschberger E, Ruetten A, Ruivenkamp C, Lopriore E, Zutt M, et al. Postzygotic HRAS and KRAS mutations cause nevus sebaceous and Schimmelpenning syndrome. Nat Genet 2012;44:783e7. Groesser L, Herschberger E, Sagrera A, Shwayder T, Flux K, Ehmann L, et al. Phacomatosis pigmentokeratotica is caused by a postzygotic HRAS mutation in a multipotent progenitor cell. J Invest Dermatol 2013;133: 1998e2003. Guarneri C, Lentini M, Cannavo` SP, Happle R. A case of hypertrichotic smooth muscle hamartoma: is it an amelanotic Becker naevus? Clin Exp Dermatol 2015;40:577e9. Gunning PW, Ghoshdastider U, Whitaker S, Popp D, Robinson RC. The evolution of compositionally and functionally distinct acting filaments. J Cell Sci 2015;128:2009e19. Happle R. Paradominant inheritance: a possible explanation for Becker’s pigmented hairy nevus. Eur J Dermatol 1992;2:39e40. Happle R. Phacomatosis pigmentokeratotica is a “pseudodidymosis”. J Invest Dermatol 2013;133:1923e5. Happle R. Mosaicism in human skin: understanding nevi, nevoid skin disorders, and cutaneous neoplasia. Berlin: Springer; 2014. Happle R, Koopman RJ. Becker nevus syndrome. Am J Med Genet 1997;68:357e61. Jain HC, Fisher BK. Familial Becker’s nevus. Int J Dermatol 1989;28:263e4.
COMMENTARY Kurek KC, Luks VL, Ayturk UM, Alomari AI, Fishman SJ, Spencer SA, et al. Somatic mosaic activating mutations in PIK3CA cause CLOVES syndrome. Am J Hum Genet 2012;90: 1108e15. Lindhurst MJ, Sapp JC, Teer JK, Johnston JJ, Finn EM, Peters K, et al. A mosaic activating mutation in AKT1 associated with the Proteus syndrome. N Engl J Med 2011;365:611e9. Maessen-Visch MB, Hulsmans RF, Hulsmans FJ, Neumann HA. Melanosis naeviformis of Becker and scoliosis: a coincidence? Acta Derm Venereol 1997;77:135e6. Panizzon R, Schnyder UW. Familial Becker’s nevus. Dermatologica 1988;176:275e6. Pansuriya TC, van Eijk R, d’Adamo P, van Ruler MA, Kuijjer ML, Oosting J, et al. Somatic mosaic IDH1 and IDH2 mutations are associated with enchondroma and spindle cell hemangioma in Ollier disease and Maffucci syndrome. Nat Genet 2011;43: 1256e61. Peacock JD, Dykema KJ, Toriello HV, Mooney MR, Scholten DJ II, Winn ME, et al.
Oculoectodermal syndrome is a mosaic RASopathy associated with KRAS alterations. Am J Med Genet A 2015;167:1429e35. Procaccio V, Salazar G, Ono S, Styers ML, Gearing M, Davila A, et al. A mutation of betaactin that alters depolymerization dynamics is associated with autosomal dominant developmental malformations, deafness, and dystonia. Am J Hum Genet 2006;78:947e60.
Siemens HW. Die naevusa¨ hnliche Melanose (Melanosis naeviformis, alias Naevus pigmentosus tardus) [The nevus-like melanosis (melanosis naeviformis, alias nevus pigmentosus tardus]. Hautarzt 1967;18: 299e303. Stevenson VA, Theurkauf WE. Actin cytoskeleton: putting a CAP on actin polymerization. Curr Biol 2000;10:R695e7.
Rivie`re JB, Mirzaa GM, O’Roak BJ, Beddaoui M, Alcantara D, Conway RL, et al. De novo germline and postzygotic mutations in AKT3, PIK3R2 and PIK3CA cause a spectrum of related megalencephaly syndromes. Nat Genet 2012a;44:934e40.
Thomas AC, Zeng Z, Rivie`re JB, O’Shaughnessy R, Al-Olabi L, St-Onge J, et al. Mosaic activating mutations in GNA11 and GNAQ are associated with phakomatosis pigmentovascularis and extensive dermal melanocytosis. J Invest Dermatol 2016;136:770e8.
Rivie`re JB, van Bon BWM, Hoischen A, Kholmanskikh S, O’Roak BJ, Gilissen C, et al. De novo mutations in the actin genes ACTB and ACTG1 cause Baraitser-Winter syndrome. Nature Genet 2012b;44:440e4.
Verloes A, Di Donato N, Masliah-Planchon J, Jongmans M, Abdul-Raman OA, Albrecht B, et al. Baraitser-Winter cerebrofrontofacial syndrome: delineation of the spectrum in 42 cases. Eur J Hum Genet 2015;23:292e301.
Shirley MD, Tang H, Gallione CJ, Baugher JD, Frelin LP, Cohen B, et al. Sturge-Weber syndrome and port-wine stains caused by somatic mutation in GNAQ. N Engl J Med 2013;368: 1971e9.
Weinstein LS, Shenker A, Gejman PV, Merino MJ, Friedman E, Spiegel AM. Activating mutations of the stimulatory G protein in the McCuneAlbright syndrome. N Engl J Med 1991;325: 1688e95.
www.jidonline.org
3