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Multiple lentigines

MedGen UID:
272242
Concept ID:
C1328931
Disease or Syndrome
Synonym: Liver spots
 
HPO: HP:0001003

Definition

Presence of an unusually high number of lentigines (singular [from HPO]

Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  
  • CROGVMultiple lentigines

Conditions with this feature

Hereditary spastic paraplegia 23
MedGen UID:
167094
Concept ID:
C0796019
Disease or Syndrome
Spastic paraplegia-23 (SPG23) is an autosomal recessive neurologic disorder characterized by childhood-onset spastic paraplegia resulting in gait difficulties and associated with pigmentary abnormalities, including premature graying of the hair and vitiligo-like or hyperpigmented skin lesions. Some patients may also have a peripheral neuropathy (summary by Lee et al., 2017).
Cardio-facio-cutaneous syndrome
MedGen UID:
266149
Concept ID:
C1275081
Disease or Syndrome
Cardiofaciocutaneous (CFC) syndrome is characterized by cardiac abnormalities (pulmonic stenosis and other valve dysplasias, septal defects, hypertrophic cardiomyopathy, rhythm disturbances), distinctive craniofacial appearance, and cutaneous abnormalities (including xerosis, hyperkeratosis, ichthyosis, keratosis pilaris, ulerythema ophryogenes, eczema, pigmented moles, hemangiomas, and palmoplantar hyperkeratosis). The hair is typically sparse, curly, fine or thick, woolly or brittle; eyelashes and eyebrows may be absent or sparse. Nails may be dystrophic or fast growing. Some form of neurologic and/or cognitive delay (ranging from mild to severe) is seen in all affected individuals. Neoplasia, mostly acute lymphoblastic leukemia, has been reported in some individuals.
Arterial dissection-lentiginosis syndrome
MedGen UID:
325345
Concept ID:
C1838122
Disease or Syndrome
A rare association syndrome, reported in several members of two families to date, characterized by arterial dissection, occurring at an early age and presenting with a range of manifestations depending on the vascular territory involved (ex. headache, dysphasia, hemiparesis), in association with cystic medial necrosis and multiple lentigines (brown and black in color and mainly affecting the skin of the trunk and extremities).
Hyperpigmentation with or without hypopigmentation, familial progressive
MedGen UID:
333550
Concept ID:
C1840392
Disease or Syndrome
Familial progressive hyperpigmentation with or without hypopigmentation (FPHH) is characterized by diffuse hyperpigmentation of variable intensity sometimes associated with cafe-au-lait macules and larger hypopigmented ash-leaf macules. These features, which involve the face, neck, trunk, and limbs, are seen at birth or develop early in infancy (summary by Wang et al., 2009 and Amyere et al., 2011). Also see familial progressive hyperpigmentation (FPH1; 614233).
Gastrocutaneous syndrome
MedGen UID:
338154
Concept ID:
C1850899
Disease or Syndrome
A rare syndromic hyperpigmentation of the skin with characteristics of multiple lentigines and cafe-au-lait spots associated with hiatal hernia and peptic ulcer, hypertelorism and myopia. There have been no further descriptions in the literature since 1982.
LEOPARD syndrome 2
MedGen UID:
370588
Concept ID:
C1969056
Disease or Syndrome
Noonan syndrome with multiple lentigines (NSML) is a condition in which the cardinal features consist of lentigines, hypertrophic cardiomyopathy, short stature, pectus deformity, and dysmorphic facial features including widely spaced eyes and ptosis. Multiple lentigines present as dispersed flat, black-brown macules, mostly on the face, neck, and upper part of the trunk with sparing of the mucosa. In general, lentigines do not appear until age four to five years but then increase to the thousands by puberty. Some individuals with NSML do not exhibit lentigines. Approximately 85% of affected individuals have heart defects, including hypertrophic cardiomyopathy (typically appearing during infancy and sometimes progressive) and pulmonary valve stenosis. Postnatal growth restriction resulting in short stature occurs in fewer than 50% of affected persons, although most affected individuals have a height that is less than the 25th centile for age. Sensorineural hearing deficits, present in approximately 20% of affected individuals, are poorly characterized. Intellectual disability, typically mild, is observed in approximately 30% of persons with NSML.
Noonan syndrome 5
MedGen UID:
370589
Concept ID:
C1969057
Disease or Syndrome
Noonan syndrome (NS) is characterized by characteristic facies, short stature, congenital heart defect, and developmental delay of variable degree. Other findings can include broad or webbed neck, unusual chest shape with superior pectus carinatum and inferior pectus excavatum, cryptorchidism, varied coagulation defects, lymphatic dysplasias, and ocular abnormalities. Although birth length is usually normal, final adult height approaches the lower limit of normal. Congenital heart disease occurs in 50%-80% of individuals. Pulmonary valve stenosis, often with dysplasia, is the most common heart defect and is found in 20%-50% of individuals. Hypertrophic cardiomyopathy, found in 20%-30% of individuals, may be present at birth or develop in infancy or childhood. Other structural defects include atrial and ventricular septal defects, branch pulmonary artery stenosis, and tetralogy of Fallot. Up to one fourth of affected individuals have mild intellectual disability, and language impairments in general are more common in NS than in the general population.
Carney complex, type 1
MedGen UID:
388559
Concept ID:
C2607929
Disease or Syndrome
Carney complex (CNC) is characterized by skin pigmentary abnormalities, myxomas, endocrine tumors or overactivity, and schwannomas. Pale brown to black lentigines are the most common presenting feature of CNC and typically increase in number at puberty. Cardiac myxomas occur at a young age, may occur in any or all cardiac chambers, and can manifest as intracardiac obstruction of blood flow, embolic phenomenon, and/or heart failure. Other sites for myxomas include the skin, breast, oropharynx, and female genital tract. Primary pigmented nodular adrenocortical disease (PPNAD), which causes Cushing syndrome, is the most frequently observed endocrine tumor in CNC, occurring in approximately 25% of affected individuals. Large-cell calcifying Sertoli cell tumors (LCCSCTs) are observed in one third of affected males within the first decade and in most adult males. Up to 75% of individuals with CNC have multiple thyroid nodules, most of which are nonfunctioning thyroid follicular adenomas. Clinically evident acromegaly from a growth hormone (GH)-producing adenoma is evident in approximately 10% of adults. Psammomatous melanotic schwannoma (PMS), a rare tumor of the nerve sheath, occurs in an estimated 10% of affected individuals. The median age of diagnosis is 20 years.
Noonan syndrome 6
MedGen UID:
413028
Concept ID:
C2750732
Disease or Syndrome
Noonan syndrome (NS) is characterized by characteristic facies, short stature, congenital heart defect, and developmental delay of variable degree. Other findings can include broad or webbed neck, unusual chest shape with superior pectus carinatum and inferior pectus excavatum, cryptorchidism, varied coagulation defects, lymphatic dysplasias, and ocular abnormalities. Although birth length is usually normal, final adult height approaches the lower limit of normal. Congenital heart disease occurs in 50%-80% of individuals. Pulmonary valve stenosis, often with dysplasia, is the most common heart defect and is found in 20%-50% of individuals. Hypertrophic cardiomyopathy, found in 20%-30% of individuals, may be present at birth or develop in infancy or childhood. Other structural defects include atrial and ventricular septal defects, branch pulmonary artery stenosis, and tetralogy of Fallot. Up to one fourth of affected individuals have mild intellectual disability, and language impairments in general are more common in NS than in the general population.
LEOPARD syndrome 3
MedGen UID:
462321
Concept ID:
C3150971
Disease or Syndrome
Noonan syndrome with multiple lentigines (NSML) is a condition in which the cardinal features consist of lentigines, hypertrophic cardiomyopathy, short stature, pectus deformity, and dysmorphic facial features including widely spaced eyes and ptosis. Multiple lentigines present as dispersed flat, black-brown macules, mostly on the face, neck, and upper part of the trunk with sparing of the mucosa. In general, lentigines do not appear until age four to five years but then increase to the thousands by puberty. Some individuals with NSML do not exhibit lentigines. Approximately 85% of affected individuals have heart defects, including hypertrophic cardiomyopathy (typically appearing during infancy and sometimes progressive) and pulmonary valve stenosis. Postnatal growth restriction resulting in short stature occurs in fewer than 50% of affected persons, although most affected individuals have a height that is less than the 25th centile for age. Sensorineural hearing deficits, present in approximately 20% of affected individuals, are poorly characterized. Intellectual disability, typically mild, is observed in approximately 30% of persons with NSML.
Cardiofaciocutaneous syndrome 4
MedGen UID:
815337
Concept ID:
C3809007
Disease or Syndrome
Cardiofaciocutaneous (CFC) syndrome is characterized by cardiac abnormalities (pulmonic stenosis and other valve dysplasias, septal defects, hypertrophic cardiomyopathy, rhythm disturbances), distinctive craniofacial appearance, and cutaneous abnormalities (including xerosis, hyperkeratosis, ichthyosis, keratosis pilaris, ulerythema ophryogenes, eczema, pigmented moles, hemangiomas, and palmoplantar hyperkeratosis). The hair is typically sparse, curly, fine or thick, woolly or brittle; eyelashes and eyebrows may be absent or sparse. Nails may be dystrophic or fast growing. Some form of neurologic and/or cognitive delay (ranging from mild to severe) is seen in all affected individuals. Neoplasia, mostly acute lymphoblastic leukemia, has been reported in some individuals.
Noonan syndrome-like disorder with loose anagen hair 1
MedGen UID:
1379805
Concept ID:
C4478716
Disease or Syndrome
Noonan syndrome-like disorder with loose anagen hair is characterized by facial features similar to those observed in Noonan syndrome (163950), including hypertelorism, ptosis, downslanting palpebral fissures, low-set posteriorly angulated ears, and overfolded pinnae. In addition, patients display short stature, frequently with growth hormone (GH; see 139250) deficiency; cognitive deficits; relative macrocephaly; small posterior fossa resulting in Chiari I malformation; hypernasal voice; cardiac defects, especially dysplasia of the mitral valve and septal defects; and ectodermal abnormalities, in which the most characteristic feature is the hair anomaly, including easily pluckable, sparse, thin, slow-growing hair (summary by Bertola et al., 2017). Reviews Komatsuzaki et al. (2010) reviewed the clinical manifestations of patients with Noonan syndrome, Costello syndrome (218040), and cardiofaciocutaneous syndrome (CFC; see 115150) compared to patients with mutations in the SHOC2 gene. They noted that although there is phenotypic overlap among the disorders, loose anagen/easily pluckable hair had not been reported in mutation-positive patients with Noonan, CFC, or Costello syndrome, and appeared to be a distinctive feature of SHOC2 mutation-positive patients. Genetic Heterogeneity of Noonan Syndrome-Like Disorder with Loose Anagen Hair NSLH2 (617506) is caused by mutation in the PPP1CB gene (600590) on chromosome 2p23.
LEOPARD syndrome 1
MedGen UID:
1631694
Concept ID:
C4551484
Disease or Syndrome
Noonan syndrome with multiple lentigines (NSML) is a condition in which the cardinal features consist of lentigines, hypertrophic cardiomyopathy, short stature, pectus deformity, and dysmorphic facial features including widely spaced eyes and ptosis. Multiple lentigines present as dispersed flat, black-brown macules, mostly on the face, neck, and upper part of the trunk with sparing of the mucosa. In general, lentigines do not appear until age four to five years but then increase to the thousands by puberty. Some individuals with NSML do not exhibit lentigines. Approximately 85% of affected individuals have heart defects, including hypertrophic cardiomyopathy (typically appearing during infancy and sometimes progressive) and pulmonary valve stenosis. Postnatal growth restriction resulting in short stature occurs in fewer than 50% of affected persons, although most affected individuals have a height that is less than the 25th centile for age. Sensorineural hearing deficits, present in approximately 20% of affected individuals, are poorly characterized. Intellectual disability, typically mild, is observed in approximately 30% of persons with NSML.
Noonan syndrome 13
MedGen UID:
1761918
Concept ID:
C5436773
Disease or Syndrome
Noonan syndrome (NS) is characterized by characteristic facies, short stature, congenital heart defect, and developmental delay of variable degree. Other findings can include broad or webbed neck, unusual chest shape with superior pectus carinatum and inferior pectus excavatum, cryptorchidism, varied coagulation defects, lymphatic dysplasias, and ocular abnormalities. Although birth length is usually normal, final adult height approaches the lower limit of normal. Congenital heart disease occurs in 50%-80% of individuals. Pulmonary valve stenosis, often with dysplasia, is the most common heart defect and is found in 20%-50% of individuals. Hypertrophic cardiomyopathy, found in 20%-30% of individuals, may be present at birth or develop in infancy or childhood. Other structural defects include atrial and ventricular septal defects, branch pulmonary artery stenosis, and tetralogy of Fallot. Up to one fourth of affected individuals have mild intellectual disability, and language impairments in general are more common in NS than in the general population.

Professional guidelines

PubMed

Yi JS, Perla S, Bennett AM
Cardiovasc Drugs Ther 2023 Dec;37(6):1193-1204. Epub 2022 Feb 14 doi: 10.1007/s10557-022-07324-0. PMID: 35156148
Kavamura MI, Leoni C, Neri G
Am J Med Genet C Semin Med Genet 2022 Dec;190(4):452-458. Epub 2022 Dec 21 doi: 10.1002/ajmg.c.32027. PMID: 36541891
Gelb BD, Yohe ME, Wolf C, Andelfinger G
Am J Med Genet C Semin Med Genet 2022 Dec;190(4):541-560. Epub 2022 Dec 19 doi: 10.1002/ajmg.c.32024. PMID: 36533679Free PMC Article

Recent clinical studies

Etiology

Gelb BD, Yohe ME, Wolf C, Andelfinger G
Am J Med Genet C Semin Med Genet 2022 Dec;190(4):541-560. Epub 2022 Dec 19 doi: 10.1002/ajmg.c.32024. PMID: 36533679Free PMC Article
Zenker M
Am J Med Genet C Semin Med Genet 2022 Dec;190(4):414-424. Epub 2022 Nov 25 doi: 10.1002/ajmg.c.32015. PMID: 36428239
Palit A, Inamadar AC
Indian J Dermatol Venereol Leprol 2022 May-Jun;88(4):452-463. doi: 10.25259/IJDVL_799_20. PMID: 35138057
Rosser T
Continuum (Minneap Minn) 2018 Feb;24(1, Child Neurology):96-129. doi: 10.1212/CON.0000000000000562. PMID: 29432239
Rauen KA
Annu Rev Genomics Hum Genet 2013;14:355-69. Epub 2013 Jul 15 doi: 10.1146/annurev-genom-091212-153523. PMID: 23875798Free PMC Article

Diagnosis

Kavamura MI, Leoni C, Neri G
Am J Med Genet C Semin Med Genet 2022 Dec;190(4):452-458. Epub 2022 Dec 21 doi: 10.1002/ajmg.c.32027. PMID: 36541891
Delogu AB, Limongelli G, Versacci P, Adorisio R, Kaski JP, Blandino R, Maiolo S, Monda E, Putotto C, De Rosa G, Chatfield KC, Gelb BD, Calcagni G
Am J Med Genet C Semin Med Genet 2022 Dec;190(4):440-451. Epub 2022 Nov 21 doi: 10.1002/ajmg.c.32014. PMID: 36408797
Palit A, Inamadar AC
Indian J Dermatol Venereol Leprol 2022 May-Jun;88(4):452-463. doi: 10.25259/IJDVL_799_20. PMID: 35138057
Rosser T
Continuum (Minneap Minn) 2018 Feb;24(1, Child Neurology):96-129. doi: 10.1212/CON.0000000000000562. PMID: 29432239
Sarkozy A, Digilio MC, Dallapiccola B
Orphanet J Rare Dis 2008 May 27;3:13. doi: 10.1186/1750-1172-3-13. PMID: 18505544Free PMC Article

Therapy

Chaput D, Andelfinger G
Can J Cardiol 2024 May;40(5):789-799. Epub 2024 Mar 1 doi: 10.1016/j.cjca.2024.02.020. PMID: 38432396
Rauen KA, Alsaegh A, Ben-Shachar S, Berman Y, Blakeley J, Cordeiro I, Elgersma Y, Evans DG, Fisher MJ, Frayling IM, George J, Huson SM, Kerr B, Khire U, Korf B, Legius E, Messiaen L, van Minkelen R, Nampoothiri S, Ngeow J, Parada LF, Phadke S, Pillai A, Plotkin SR, Puri R, Raji A, Ramesh V, Ratner N, Shankar SP, Sharda S, Tambe A, Vikkula M, Widemann BC, Wolkenstein P, Upadhyaya M
Am J Med Genet A 2019 Jun;179(6):1091-1097. Epub 2019 Mar 25 doi: 10.1002/ajmg.a.61125. PMID: 30908877Free PMC Article
Levin MD, Saitta SC, Gripp KW, Wenger TL, Ganesh J, Kalish JM, Epstein MR, Smith R, Czosek RJ, Ware SM, Goldenberg P, Myers A, Chatfield KC, Gillespie MJ, Zackai EH, Lin AE
Am J Med Genet A 2018 Aug;176(8):1711-1722. Epub 2018 Jul 28 doi: 10.1002/ajmg.a.38854. PMID: 30055033Free PMC Article
McWilliams GD, SantaCruz K, Hart B, Clericuzio C
Am J Med Genet A 2016 Jan;170A(1):195-201. Epub 2015 Sep 17 doi: 10.1002/ajmg.a.37379. PMID: 26377682
Yeoh TY, Wittwer ED, Weingarten TN, Sprung J
J Cardiothorac Vasc Anesth 2014 Oct;28(5):1243-50. Epub 2014 Jan 23 doi: 10.1053/j.jvca.2013.09.015. PMID: 24461361

Prognosis

Boleti O, Norrish G, Field E, Dady K, Summers K, Nepali G, Bhole V, Uzun O, Wong A, Daubeney PEF, Stuart G, Fernandes P, McLeod K, Ilina M, Ali MNL, Bharucha T, Donne GD, Brown E, Linter K, Jones CB, Searle J, Regan W, Mathur S, Boyd N, Reinhardt Z, Duignan S, Prendiville T, Adwani S, Kaski JP
ESC Heart Fail 2024 Apr;11(2):923-936. Epub 2024 Jan 13 doi: 10.1002/ehf2.14637. PMID: 38217456Free PMC Article
Guo K, Liu JW, Zhang R, Wang R, Ma DL, Zhang X
Pigment Cell Melanoma Res 2023 May-Jul;36(3-4):288-298. Epub 2023 Apr 13 doi: 10.1111/pcmr.13086. PMID: 37056170
Delogu AB, Limongelli G, Versacci P, Adorisio R, Kaski JP, Blandino R, Maiolo S, Monda E, Putotto C, De Rosa G, Chatfield KC, Gelb BD, Calcagni G
Am J Med Genet C Semin Med Genet 2022 Dec;190(4):440-451. Epub 2022 Nov 21 doi: 10.1002/ajmg.c.32014. PMID: 36408797
Yue X, Zhao X, Dai Y, Yu L
Hereditas 2021 Sep 6;158(1):34. doi: 10.1186/s41065-021-00199-5. PMID: 34488904Free PMC Article
Sarkozy A, Digilio MC, Dallapiccola B
Orphanet J Rare Dis 2008 May 27;3:13. doi: 10.1186/1750-1172-3-13. PMID: 18505544Free PMC Article

Clinical prediction guides

Boleti O, Norrish G, Field E, Dady K, Summers K, Nepali G, Bhole V, Uzun O, Wong A, Daubeney PEF, Stuart G, Fernandes P, McLeod K, Ilina M, Ali MNL, Bharucha T, Donne GD, Brown E, Linter K, Jones CB, Searle J, Regan W, Mathur S, Boyd N, Reinhardt Z, Duignan S, Prendiville T, Adwani S, Kaski JP
ESC Heart Fail 2024 Apr;11(2):923-936. Epub 2024 Jan 13 doi: 10.1002/ehf2.14637. PMID: 38217456Free PMC Article
Monda E, Prosnitz A, Aiello R, Lioncino M, Norrish G, Caiazza M, Drago F, Beattie M, Tartaglia M, Russo MG, Colan SD, Calcagni G, Gelb BD, Kaski JP, Roberts AE, Limongelli G
Circ Genom Precis Med 2023 Aug;16(4):350-358. Epub 2023 May 18 doi: 10.1161/CIRCGEN.122.003861. PMID: 37199218
Galazka P, Jain R, Muthukumar L, Sanders H, Bush M, Jan MF, Jahangir A, Khandheria BK, Tajik AJ
Am J Cardiol 2020 Nov 15;135:168-173. Epub 2020 Aug 28 doi: 10.1016/j.amjcard.2020.08.027. PMID: 32866449
Calcagni G, Gagliostro G, Limongelli G, Unolt M, De Luca E, Digilio MC, Baban A, Albanese SB, Ferrero GB, Baldassarre G, Agnoletti G, Banaudi E, Marek J, Kaski JP, Tuo G, Marasini M, Cairello F, Madrigali A, Pacileo G, Russo MG, Milanesi O, Formigari R, Brighenti M, Ragni L, Donti A, Drago F, Dallapiccola B, Tartaglia M, Marino B, Versacci P
Birth Defects Res 2020 Jun;112(10):725-731. doi: 10.1002/bdr2.1670. PMID: 32558384
Porciello R, Divona L, Strano S, Carbone A, Calvieri C, Giustini S
Dermatol Online J 2008 Mar 15;14(3):7. PMID: 18627709

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