Abstract
Though melanocytic nevi are ubiquitous in the general population, they can also be
key cutaneous manifestations of genetic syndromes. We describe genodermatoses associated
with melanocytic nevi and discuss their clinical characteristics, cutaneous manifestations,
underlying genetics, and, if applicable, guidelines for when genetic testing should
be performed. We categorized these genodermatoses based on their association with
congenital nevi, acquired nevi, or nevi whose first appearance is unknown. In many
cases, the distinctive morphology or distribution of melanocytic nevi can be an important
clue that an underlying genetic syndrome is present, allowing both the patient as
well as family members to be screened for the more serious complications of their
genetic disorder and receive education on potential preventative measures. As we continue
to advance our understanding of how various genotypes give rise to the wide spectrum
of phenotypes observed in these genodermatoses, we shall be able to better stratify
risk and tailor our screening methods to clinically manage the heterogeneous manifestations
of genodermatoses among these patients.
To read this article in full you will need to make a payment
Purchase one-time access:
Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online accessOne-time access price info
- For academic or personal research use, select 'Academic and Personal'
- For corporate R&D use, select 'Corporate R&D Professionals'
Subscribe:
Subscribe to Clinics in DermatologyAlready a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
References
- Update on melanocytic nevi in children.Clin Dermatol. 2015; 33: 368-386
- Syndromes associated with melanocytic nevi.J Am Acad Dermatol. 1993; 29: 373-388
- Color Atlas of Melanocytic Lesions of the Skin.Springer, Berlin, Germany2007: 1-351
- Carney complex: an update.Eur J Endocrinol. 2015; 173: M85-M97
- Next generation immunohistochemistry: emerging substitutes to genetic testing?.Semin Diagn Pathol. 2018; 35: 161-169
- Clinical and molecular features of the Carney complex: patient evaluation.J Clin Endocrinol Metab. 2001; 86: 4041-4046
- Heterogeneity of skin manifestations in patients with Carney complex.J Am Acad Dermatol. 2008; 59: 801-810
- Skin manifestations of endocrine and neuroendocrine tumors.Semin Oncol. 2016; 43: 335-340
- Carney complex and lentiginosis.Pigment Cell Melanoma Res. 2009; 22: 580-587
- Deletions of the PRKAR1A locus at 17q24.2-q24.3 in Carney complex: genotype-phenotype correlations and implications for genetic testing.J Clin Endocrinol Metab. 2014; 99: E183-E188
- Skin markers of occult spinal dysraphism in children: a review of 54 cases.Arch Dermatol. 2004; 140: 1109-1115
- Occult spinal dysraphism in the presence of rare cutaneous stigma in a neonate: importance of ultrasound and magnetic resonance imaging.Case Rep Med. 2013; 2013468376
- Cutaneous stigmata of occult spinal dysraphism.J Neonatal Surg. 2013; 2: 15
- Use of magnetic resonance imaging to detect occult spinal dysraphism in infants.J Neurosurg Pediatr. 2017; 19: 217-226
- The effect of surgery for split spinal cord malformation on neurologic and urologic function.Pediatr Neurosurg. 2000; 32: 13-19
- Spinal dysraphism: a neurosurgical review for the urologist.Rev Urol. 2009; 11: 71-81
- Use of magnetic resonance imaging to detect occult spinal dysraphism in infants.J Neurosurg. 2017; 19: 217-226
- Spinal ultrasound in patients with anorectal malformations: is this the end of an era?.Pediatr Surg Int. 2014; 30: 829-831
- Screening for spinal dysraphisms in newborns with sacral dimples.Clin Pediatr (Phila). 2016; 55: 1064-1070
- The accuracy of abnormal lumbar sonography findings in detecting occult spinal dysraphism: a comparison with magnetic resonance imaging.J Neurosurg Pediatr. 2012; 10: 150-153
- Let's call it “Crouzonodermoskeletal syndrome” so we won't be prisoners of our own conventional terminology.Am J Med Genet. 1999; 84 (74-74)
- Fibroblast growth factor receptor 3 (FGFR3) transmembrane mutation in Crouzon syndrome with acanthosis nigricans.Nat Genet. 1995; 11: 462-464
- Crouzon disease with acanthosis nigricans and melanocytic nevi.Pediatr Dermatol. 1996; 13: 18-21
- Cutaneous features of Crouzon syndrome with acanthosis nigricans.JAMA Dermatology. 2013; 149: 737-741
- Crouzon with acanthosis nigricans. Further delineation of the syndrome.Clin Genet. 2007; 72: 405-410
- Multiple congenital melanocytic nevi and neurocutaneous melanosis are caused by postzygotic mutations in codon 61 of NRAS.J Invest Dermatol. 2013; 133: 2229-2236
- Large congenital melanocytic nevi and neurocutaneous melanocytosis: one pediatric center's experience.J Am Acad Dermatol. 2009; 61: 766-774
- Neurocutaneous melanosis: definition and review of the literature.J Am Acad Dermatol. 1991; 24: 747-755
- The risk of melanoma and neurocutaneous melanosis associated with congenital melanocytic nevi.Semin Cutan Med Surg. 2010; 29: 159-164
- Number of satellite nevi as a correlate for neurocutaneous melanocytosis in patients with large congenital melanocytic nevi.Arch Dermatol. 2004; 140: 171-175
- Complications of congenital melanocytic naevi in children: analysis of 16 years’ experience and clinical practice.Br J Dermatol. 2008; 159: 907-914
- New insights into neurocutaneous melanosis.Pediatr Radiol. 2018; 48: 1786-1796
- Neurocutaneous melanosis: clinical features of large congenital melanocytic nevi in patients with manifest central nervous system melanosis.J Am Acad Dermatol. 1996; 35: 529-538
- Association of melanoma and neurocutaneous melanocytosis with large congenital melanocytic naevi—results from the NYU-LCMN registry.Br J Dermatol. 2005; 152: 512-517
- Benign melanocytic neoplasms. 4th ed. Philadelphia: Elsevier, 2018: 1954-1988
- Spectrum of central nervous system abnormalities in neurocutaneous melanocytosis.Dev Med Child Neurol. 2012; 54: 563-568
- Giant congenital melanocytic nevi: the significance of neurocutaneous melanosis in neurologically asymptomatic children.Plast Reconstr Surg. 2001; 107: 933-941
- Feed and wrap MRI technique in infants.Clin Pediatr (Phila). 2017; 56: 1095-1103
- Genetics of neural crest and neurocutaneous syndromes.Handb Clin Neurol. 2013; 111: 309-314
- Somatic KRAS mutation in an infant with linear nevus sebaceous syndrome associated with lymphatic malformations.Medicine (Baltimore). 2017; 96: e8016
- Phenotype/genotype correlations in epidermal nevus syndrome as a neurocristopathy.Handb Clin Neurol. 2015; 132: 9-25
- Epidermal nevi and the epidermal nevus syndrome.J Am Acad Dermatol. 1989; 20: 476-488
- Mosaic activating RAS mutations in nevus sebaceus and nevus sebaceus syndrome.J Invest Dermatol. 2013; 133: 824-827
- Genetic and clinical mosaicism in a type of epidermal nevus.N Engl J Med. 1994; 331: 1408-1415
- Whole-exome sequencing reveals somatic mutations in HRAS and KRAS, which cause nevus sebaceus.J Invest Dermatol. 2013; 133: 827-830
- Secondary neoplasms associated with nevus sebaceus of Jadassohn: a study of 707 cases.J Am Acad Dermatol. 2014; 70: 332-337
- Naevus sebaceus: a mosaic RASopathy.Clin Exp Dermatol. 2014; 39: 1-6
- Sebaceous lesions and their associated syndromes: part II.J Am Acad Dermatol. 2009; 61: 563-580
- A postzygotic NRAS mutation in a patient with Schimmelpenning syndrome.Am J Med Genet Part A. 2015; 167A: 2223-2225
- Discordance for Schimmelpenning-Feuerstein-Mims syndrome in monochorionic twins supports the concept of a postzygotic mutation.Am J Med Genet A. 2010; 152A: 2816-2819
- Nevus sebaceus: a clinicopathological study of 168 cases and review of the literature.Int J Dermatol. 2016; 55: 193-200
- Epidermodysplasia verruciformis-associated and genital-mucosal high-risk human papillomavirus DNA are prevalent in nevus sebaceus of Jadassohn.J Am Acad Dermatol. 2008; 59: 279-294
- Human papilloma virus is not prevalent in nevus sebaceus.Pediatr Dermatol. 2014; 31: 326-330
- Phacomatosis pigmentovascularis revisited and reclassified.Arch Dermatol. 2005; 141: 385-388
- Phakomatosis pigmentovascularis: clinical findings in 15 patients and review of the literature.J Am Acad Dermatol. 2008; 58: 88-93
- Vascular malformations.in: Bolognia JL Schaffer JV Cerroni L Dermatology. 4th ed. Elsevier, Philadelphia2018: 1805-1827
- Mosaic activating mutations in GNA11 and GNAQ are associated with phakomatosis pigmentovascularis and extensive dermal melanocytosis.J Invest Dermatol. 2016; 136: 770-778
Mize DE, Bishop M, Resse E, Sluzevich J. Familial atypical multiple mole melanoma syndrome. Available at: https://www.ncbi.nlm.nih.gov/books/NBK7030/pdf/Bookshelf_NBK7030.pdf. Accessed December 12, 2018.
- Hereditary melanoma: update on syndromes and management: genetics of familial atypical multiple mole melanoma syndrome.J Am Acad Dermatol. 2016; 74: 395-410
- Pathology of Pigmented Skin Lesions.Springer Berlin Heidelberg, Berlin, Germany2017
- Identification, genetic testing, and management of hereditary melanoma.Cancer Metastasis Rev. 2017; 36: 77-90
- Homozygotes for CDKN2 (p16) germline mutation in Dutch familial melanoma kindreds.Nat Genet. 1995; 10: 351-353
- Germline p16 mutations in familial melanoma.Nat Genet. 1994; 8: 15-21
- Melanoma susceptibility genes and risk assessment.Methods Mol Biol. 2014; 1102: 381-393
- Phenotypic variation in eight extended CDKN2A germline mutation familial atypical multiple mole melanoma-pancreatic carcinoma-prone families: the familial atypical mole melanoma-pancreatic carcinoma syndrome.Cancer. 2002; 94: 84-96
- Clinical and histopathological features of malignant melanoma in germline CDKN2A mutation families.Melanoma Res. 2002; 12: 549-557
- Body site of cutaneous malignant melanoma-a study on patients with hereditary and multiple sporadic tumours.Melanoma Res. 2003; 13: 279-286
- Selection criteria for genetic assessment of patients with familial melanoma.J Am Acad Dermatol. 2009; 61 (e1-677.e14): 677
- Ocular manifestations of genetic skin disorders.Clin Dermatol. 2016; 34: 242-275
- Deep phenotyping of 89 xeroderma pigmentosum patients reveals unexpected heterogeneity dependent on the precise molecular defect.Proc Natl Acad Sci U S A. 2016; 113: E1236-E1245
- Cancer and neurologic degeneration in xeroderma pigmentosum: long term follow-up characterises the role of DNA repair.J Med Genet. 2011; 48: 168-176
- Ocular manifestations of xeroderma pigmentosum: long-term follow-up highlights the role of DNA repair in protection from sun damage.Ophthalmology. 2013; 120: 1324-1336
- Neurological symptoms and natural course of xeroderma pigmentosum.Brain. 2008; 131: 1979-1989
- J Dermatol. 1995; 22: 360-364
- Dermoscopy of skin lesions in two patients with xeroderma pigmentosum.Br J Dermatol. 2005; 152: 271-278
- High frequency of PTEN mutations in nevi and melanomas from xeroderma pigmentosum patients.Pigment Cell Melanoma Res. 2014; 27: 454-464
- Genotypic and Phenotypic Features of BAP1 Cancer Syndrome.JAMA Dermatology. 2017; 153: 999-1006
- BAP1 and cancer.Nat Rev Cancer. 2013; 13: 153-159
- The potential role of ubiquitin c-terminal hydrolases in oncogenesis.Biochim Biophys Acta. 2010; 1806: 1-6
- Clinical and dermoscopic features of cutaneous BAP1-inactivated melanocytic tumors: results of a multicenter case-control study by the International Dermoscopy Society.J Am Acad Dermatol. 2019; 80: 1585-1593
- A distinct subset of atypical Spitz tumors is characterized by BRAF mutation and loss of BAP1 expression.Am J Surg Pathol. 2012; 36: 818-830
- Microphthalmia transcription factor expression in cutaneous benign, malignant melanocytic, and nonmelanocytic tumors.Am J Surg Pathol. 2001; 25: 51-57
- Integrative genomic analyses identify MITF as a lineage survival oncogene amplified in malignant melanoma.Nature. 2005; 436: 117-122
- Microphthalmia-associated transcription factor gene amplification in metastatic melanoma is a prognostic marker for patient survival, but not a predictive marker for chemosensitivity and chemotherapy response.Clin Cancer Res. 2007; 13: 6344-6350
- MITF accurately highlights epidermal melanocytes in atypical intraepidermal melanocytic proliferations.Am J Dermatopathol. 2013; 35: 25-29
- A novel recurrent mutation in MITF predisposes to familial and sporadic melanoma.Nature. 2011; 480: 99-103
- A SUMOylation-defective MITF germline mutation predisposes to melanoma and renal carcinoma.Nature. 2011; 480: 94-98
- Pathways from senescence to melanoma: focus on MITF sumoylation.Oncogene. 2017; 36: 6659-6667
- Phenotypic characterization of nevus and tumor patterns in MITF E318K mutation carrier melanoma patients.J Invest Dermatol. 2014; 134: 141-149
- Prevalence of MITF p.E318K in patients with melanoma independent of the presence of CDKN2A causative mutations.JAMA Dermatol. 2016; 152: 405-412
- The master role of microphthalmia-associated transcription factor in melanocyte and melanoma biology.Lab Invest. 2017; 97: 649-656
- Waardenburg syndrome type 2 caused by mutations in the human microphthalmia (MITF) gene.Nat Genet. 1994; 8: 251-255
- Tietz syndrome (hypopigmentation/deafness) caused by mutation of MITF.J Med Genet. 2000; 37: 446-448
- MITF: a stream flowing for pigment cells.Pigment Cell Res. 2000; 13: 230-240
- Clinical and cytogenetic features of 516 patients with suspected Turner syndrome—a single-center experience.J Pediatr Endocrinol Metab. 2018; 31: 167-173
- Turner's syndrome in dermatology.J Am Acad Dermatol. 2004; 50: 767-776
- Spontaneous resolution of a cystic hygroma in a fetus with Turner syndrome.Prenat Diagn. 1988; 8: 291-296
- Lymphatic vessel hypoplasia in fetuses with Turner syndrome.Hum Reprod. 1999; 14: 823-826
- Influence of genetic and environmental factors on melanocytic naevi: a lesson from Turner's syndrome.Br J Dermatol. 1998; 138: 993-997
- The XO syndrome: a study of the differentiated phenotype in 25 patients.J Pediatr. 1963; 63: 577-588
- Cancer incidence in women with Turner syndrome in Great Britain: a national cohort study.Lancet Oncol. 2008; 9: 239-246
- Nevi and melanoma: lessons from Turner's syndrome.Dermatology. 2001; 202: 1-3
- Halo nevus, rather than vitiligo, is a typical dermatologic finding of turner's syndrome: clinical, genetic, and immunogenetic study in 72 patients.J Am Acad Dermatol. 2004; 51: 354-358
- Disorders with chromosome abnormalities.Genodermatoses. 2nd ed. Lippincott Williams & Wilkins, Philadelphia2005: 346-358
- Noonan syndrome.Lancet. 2013; 381: 333-342
- Functions of Shp2 in cancer.J Cell Mol Med. 2015; 19: 2075-2083
- Cancer risk in patients with Noonan syndrome carrying a PTPN11 mutation.Eur J Hum Genet. 2011; 19: 870-874
- Cancer spectrum and frequency among children with Noonan, Costello and cardio-facio-cutaneous syndromes.Br J Cancer. 2015; 112: 1392-1397
- A case of Noonan's syndrome with possible associated neuroblastoma.Pediatr Radiol. 2000; 30: 432-433
- Noonan syndrome associated with neuroblastoma: a case report.Pediatr Radiol. 1997; 27: 324-326
- Noonan syndrome, the SOS1 gene and embryonal rhabdomyosarcoma.Genes, Chromosom Cancer. 2010; 49: 635-641
- Recommendations for cancer surveillance in individuals with RASopathies and other rare genetic conditions with increased cancer risk.Clin Cancer Res. 2017; 23: e83-e90
- Dermatological manifestations in cardiofaciocutaneous syndrome: a prospective multicentric study of 45 mutation-positive patients.Br J Dermatol. 2019; 180: 172-180
- Vitiligo and melanocytic nevi: new findings in Coffin-Siris syndrome associated with ARID1 germline mutation.JAAD Case Rep. 2019; 5: 50-53
- Coffin-Siris syndrome is a SWI/SNF complex disorder.Clin Genet. 2014; 85: 548-554
- Coffin-Siris syndrome and related disorders involving components of the BAF (mSWI/SNF) complex: historical review and recent advances using next generation sequencing.Am J Med Genet Part C Semin Med Genet. 2014; 166C: 241-251
- The ARID1B phenotype: what we have learned so far.Am J Med Genet Part C Semin Med Genet. 2014; 166: 276-289
- The role of objective facial analysis using FDNA in making diagnoses following whole exome analysis. Report of two patients with mutations in the BAF complex genes.Am J Med Genet Part A. 2016; 170: 1754-1762
- Mutations affecting components of the SWI/SNF complex cause Coffin-Siris syndrome.Nat Genet. 2012; 44: 376-378
- The genetic evolution of melanoma from precursor lesions.N Engl J Med. 2015; 373: 1926-1936
- A landscape of driver mutations in melanoma.Cell. 2012; 150: 251-263
- Ectrodactyly, ectodermal dysplasia and clefting (EEC) syndrome.J Eur Acad Dermatol Venereol. 2003; 17: 356-358
- Heterozygous germline mutations in the p53 homolog p63 are the cause of EEC syndrome.Cell. 1999; 99: 143-153
- Analysis of the p63 gene in classical EEC syndrome, related syndromes, and non-syndromic orofacial clefts.J Med Genet. 2002; 39: 559-566
- p63 is essential for regenerative proliferation in limb, craniofacial and epithelial development.Nature. 1999; 398: 714-718
- p63 is a p53 homologue required for limb and epidermal morphogenesis.Nature. 1999; 398: 708-713
- Genitourinary malformations: an under-recognized feature of ectrodactyly, ectodermal dysplasia and cleft lip/palate syndrome.Clin Dysmorphol. 2017; 26: 78-82
- Twenty-four cases of the EEC syndrome: clinical presentation and management.J Med Genet. 1995; 32: 716-723
- A new probably X-linked inherited syndrome: congenital muscular torticollis, multiple keloids cryptorchidism and renal dysplasia.Acta Genet Med Gemellol (Roma). 1968; 17: 439-467
- Clinical genetics of familial keloids.Arch Dermatol. 2001; 137: 1429-1434
- Gene mapping and serendipity. The locus for torticollis, keloids, cryptorchidism and renal dysplasia (31430, McKusick) is at Xq28, distal to the G6PD locus.Hum Genet. 1982; 62: 280-281
- Kuskokwim syndrome, a recessive congenital contracture disorder, extends the phenotype of FKBP10 mutations.Hum Mutat. 2013; 34: 1279-1288
- Arthrogryposis Syndrome (Kuskokwim disease) in the Eskimo.JAMA. 1969; 209: 1481-1486
- Etiology and pathogenesis of ectodermal dysplasias.Am J Med Genet A. 2014; 164A: 2472-2477
- Tricho-odonto-onycho-dermal dysplasia and WNT10A mutations.Am J Med Genet A. 2014; 164A: 1041-1048
- Trichoodontoonychial dysplasia—a new meso-ectodermal dysplasia.Am J Med Genet. 1983; 15: 67-70
- A recognisable short stature syndrome with premature aging and pigmented naevi.J Med Genet. 1988; 25: 53-56
- Orofacial signs and dental abnormalities in patients with Mulvihill-Smith syndrome.Medicine (Baltimore). 2018; 97: e0656
- Case report: adult phenotype of Mulvihill-Smith syndrome.Am J Med Genet Part A. 2009; 149A: 496-500
- The eleventh reported case of Mulvihill-Smith syndrome in the literature.BMC Neurol. 2014; 14: 4
- Mulvihill-Smith syndrome: case report and review.J Med Genet. 1994; 31: 707-711
- Mulvihill-Smith progeria-like syndrome: a further report with delineation of phenotype, immunologic deficits, and novel observation of fibroblast abnormalities.Am J Med Genet. 1997; 69: 56-64
- Premature aging and immunodeficiency: Mulvihill-Smith syndrome?.Am J Med Genet. 1993; 45: 597-600
- Carney complex.in: Adam MP Ardinger HH Pagon RA GeneReviews. University of Washington, Seattle, Seattle, WA2018
- Carney complex.in: Feingold KR Anawalt B Boyce A Endotext. MDText.com Inc., South Dartmouth, MA2018
National Center for Biotechnology Information Genetic Testing Registry. Available at: https://www.ncbi.nlm.nih.gov/gtr/. Accessed May 2, 2019.
- Xeroderma pigmentosum. Seattle, WA: GeneReviews.University of Washington, Seattle, Seattle, WA2016
- BAP1 tumor predisposition syndrome.in: Adam MP Ardinger HH Pagon RA GeneReviews. University of Washington, Seattle, Seattle, WA2016
- Care of girls and women with Turner syndrome: a guideline of the Turner syndrome study group.J Clin Endocrinol Metab. 2007; 92: 10-25
- Noonan syndrome.in: Adam MP Ardinger HH Pagon RA GeneReviews. University of Washington, Seattle, Seattle, WA2016
- Coffin-Siris syndrome.in: Adam MP Ardinger HH Pagon RA GeneReviews. University of Washington, Seattle, Seattle, WA2018
- TP63-related disorders.in: Adam MP Ardinger HH Pagon RA GeneReviews. WA: University of Washington, Seattle, Seattle2015
Article info
Publication history
Published online: February 14, 2022
Identification
Copyright
© 2022 Elsevier Inc. All rights reserved.
