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Cardiofaciocutaneous syndrome 2(CFC2)

MedGen UID:
815335
Concept ID:
C3809005
Disease or Syndrome
Synonyms: CFC2; KRAS-Related Cardiofaciocutaneous Syndrome
 
Gene (location): KRAS (12p12.1)
 
Monarch Initiative: MONDO:0014112
OMIM®: 615278

Disease characteristics

Excerpted from the GeneReview: Cardiofaciocutaneous 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, and woolly or brittle; eyelashes and eyebrows may be absent or sparse. Nails may be dystrophic or fast growing. Affected individuals typically have some form of neurologic and/or cognitive delay (ranging from mild to severe). Most individuals have severe feeding issues, which can contribute to poor growth, and many require nasogastric or gastrostomy tube feeding. Many affected individuals have eye findings, including strabismus, nystagmus, refractive errors, and optic nerve hypoplasia. Seizures may be present and can be refractory to therapy. [from GeneReviews]
Authors:
Katherine A Rauen   view full author information

Additional description

From OMIM
Cardiofaciocutaneous (CFC) syndrome is a multiple congenital anomaly disorder characterized by a distinctive facial appearance, heart defects, and mental retardation (summary by Niihori et al., 2006). In a phenotypic comparison of BRAF (164757)-positive and KRAS-positive individuals with CFC, Niihori et al. (2006) observed that patients with KRAS mutations did not have the skin abnormalities, such as ichthyosis, hyperkeratosis, and hemangioma, that were present in patients with BRAF mutations.  http://www.omim.org/entry/615278

Clinical features

From HPO
Mitral valve prolapse
MedGen UID:
7671
Concept ID:
C0026267
Disease or Syndrome
One or both of the leaflets (cusps) of the mitral valve bulges back into the left atrium upon contraction of the left ventricle.
Low-set ears
MedGen UID:
65980
Concept ID:
C0239234
Congenital Abnormality
Upper insertion of the ear to the scalp below an imaginary horizontal line drawn between the inner canthi of the eye and extending posteriorly to the ear.
Posteriorly rotated ears
MedGen UID:
96566
Concept ID:
C0431478
Congenital Abnormality
A type of abnormal location of the ears in which the position of the ears is characterized by posterior rotation (the superior part of the ears is rotated towards the back of the head, and the inferior part of the ears towards the front).
Global developmental delay
MedGen UID:
107838
Concept ID:
C0557874
Finding
A delay in the achievement of motor or mental milestones in the domains of development of a child, including motor skills, speech and language, cognitive skills, and social and emotional skills. This term should only be used to describe children younger than five years of age.
Peripheral axonal neuropathy
MedGen UID:
266071
Concept ID:
C1263857
Disease or Syndrome
An abnormality characterized by disruption of the normal functioning of peripheral axons.
High palate
MedGen UID:
66814
Concept ID:
C0240635
Congenital Abnormality
Height of the palate more than 2 SD above the mean (objective) or palatal height at the level of the first permanent molar more than twice the height of the teeth (subjective).
Absent eyebrow
MedGen UID:
98133
Concept ID:
C0431448
Congenital Abnormality
Absence of the eyebrow.
Anteverted nares
MedGen UID:
326648
Concept ID:
C1840077
Finding
Anteriorly-facing nostrils viewed with the head in the Frankfurt horizontal and the eyes of the observer level with the eyes of the subject. This gives the appearance of an upturned nose (upturned nasal tip).
Coarse facial features
MedGen UID:
335284
Concept ID:
C1845847
Finding
Absence of fine and sharp appearance of brows, nose, lips, mouth, and chin, usually because of rounded and heavy features or thickened skin with or without thickening of subcutaneous and bony tissues.
Broad forehead
MedGen UID:
338610
Concept ID:
C1849089
Finding
Width of the forehead or distance between the frontotemporales is more than two standard deviations above the mean (objective); or apparently increased distance between the two sides of the forehead.
Fine hair
MedGen UID:
98401
Concept ID:
C0423867
Finding
Hair that is fine or thin to the touch.
Curly hair
MedGen UID:
488919
Concept ID:
C0558165
Finding
Sparse hair
MedGen UID:
1790211
Concept ID:
C5551005
Finding
Reduced density of hairs.
Ptosis
MedGen UID:
2287
Concept ID:
C0005745
Disease or Syndrome
The upper eyelid margin is positioned 3 mm or more lower than usual and covers the superior portion of the iris (objective); or, the upper lid margin obscures at least part of the pupil (subjective).
Myopia
MedGen UID:
44558
Concept ID:
C0027092
Disease or Syndrome
Nearsightedness, also known as myopia, is an eye condition that causes blurry distance vision. People who are nearsighted have more trouble seeing things that are far away (such as when driving) than things that are close up (such as when reading or using a computer). If it is not treated with corrective lenses or surgery, nearsightedness can lead to squinting, eyestrain, headaches, and significant visual impairment.\n\nNearsightedness usually begins in childhood or adolescence. It tends to worsen with age until adulthood, when it may stop getting worse (stabilize). In some people, nearsightedness improves in later adulthood.\n\nFor normal vision, light passes through the clear cornea at the front of the eye and is focused by the lens onto the surface of the retina, which is the lining of the back of the eye that contains light-sensing cells. People who are nearsighted typically have eyeballs that are too long from front to back. As a result, light entering the eye is focused too far forward, in front of the retina instead of on its surface. It is this change that causes distant objects to appear blurry. The longer the eyeball is, the farther forward light rays will be focused and the more severely nearsighted a person will be.\n\nNearsightedness is measured by how powerful a lens must be to correct it. The standard unit of lens power is called a diopter. Negative (minus) powered lenses are used to correct nearsightedness. The more severe a person's nearsightedness, the larger the number of diopters required for correction. In an individual with nearsightedness, one eye may be more nearsighted than the other.\n\nEye doctors often refer to nearsightedness less than -5 or -6 diopters as "common myopia." Nearsightedness of -6 diopters or more is commonly called "high myopia." This distinction is important because high myopia increases a person's risk of developing other eye problems that can lead to permanent vision loss or blindness. These problems include tearing and detachment of the retina, clouding of the lens (cataract), and an eye disease called glaucoma that is usually related to increased pressure within the eye. The risk of these other eye problems increases with the severity of the nearsightedness. The term "pathological myopia" is used to describe cases in which high myopia leads to tissue damage within the eye.

Professional guidelines

PubMed

Serbinski CR, Vanderwal A, Chadwell SE, Sanchez AI, Hopkin RJ, Hufnagel RB, Weaver KN, Prada CE
Am J Med Genet A 2024 Feb;194(2):195-202. Epub 2023 Sep 29 doi: 10.1002/ajmg.a.63397. PMID: 37774117
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
Pierpont EI, Kenney-Jung DL, Shanley R, Zatkalik AL, Whitmarsh AE, Kroening SJ, Roberts AE, Zenker M
Genet Med 2022 Jul;24(7):1556-1566. Epub 2022 May 7 doi: 10.1016/j.gim.2022.04.004. PMID: 35524774

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
Pierpont EI, Kenney-Jung DL, Shanley R, Zatkalik AL, Whitmarsh AE, Kroening SJ, Roberts AE, Zenker M
Genet Med 2022 Jul;24(7):1556-1566. Epub 2022 May 7 doi: 10.1016/j.gim.2022.04.004. PMID: 35524774
Hebron KE, Hernandez ER, Yohe ME
Dis Model Mech 2022 Feb 1;15(2) Epub 2022 Feb 18 doi: 10.1242/dmm.049107. PMID: 35178568Free PMC Article
Jurcă MC, Iuhas OA, Puiu M, Chiriţă-Emandi A, Andreescu NI, Petcheşi CD, Jurcă AD, Magyar I, Jurcă SI, Kozma K, Severin EM, Bembea M
Rom J Morphol Embryol 2021 Apr-Jun;62(2):563-568. doi: 10.47162/RJME.62.2.23. PMID: 35024745Free PMC Article
Johnson B, Goldberg-Strassler D, Gripp K, Thacker M, Leoni C, Stevenson D
Am J Med Genet A 2015 Jan;167A(1):40-4. Epub 2014 Oct 24 doi: 10.1002/ajmg.a.36828. PMID: 25346259

Diagnosis

Jurcă MC, Iuhas OA, Puiu M, Chiriţă-Emandi A, Andreescu NI, Petcheşi CD, Jurcă AD, Magyar I, Jurcă SI, Kozma K, Severin EM, Bembea M
Rom J Morphol Embryol 2021 Apr-Jun;62(2):563-568. doi: 10.47162/RJME.62.2.23. PMID: 35024745Free PMC Article
Johnson B, Goldberg-Strassler D, Gripp K, Thacker M, Leoni C, Stevenson D
Am J Med Genet A 2015 Jan;167A(1):40-4. Epub 2014 Oct 24 doi: 10.1002/ajmg.a.36828. PMID: 25346259
Roberts A, Allanson J, Jadico SK, Kavamura MI, Noonan J, Opitz JM, Young T, Neri G
J Med Genet 2006 Nov;43(11):833-42. Epub 2006 Jul 6 doi: 10.1136/jmg.2006.042796. PMID: 16825433Free PMC Article
Ion A, Tartaglia M, Song X, Kalidas K, van der Burgt I, Shaw AC, Ming JE, Zampino G, Zackai EH, Dean JC, Somer M, Parenti G, Crosby AH, Patton MA, Gelb BD, Jeffery S
Hum Genet 2002 Oct;111(4-5):421-7. Epub 2002 Aug 24 doi: 10.1007/s00439-002-0803-6. PMID: 12384786
Schepis C, Greco D, Romano C
Australas J Dermatol 1999 May;40(2):111-3. doi: 10.1046/j.1440-0960.1999.00333.x. PMID: 10333626

Therapy

Bessis D, Bursztejn AC, Morice-Picard F, Capri Y, Barbarot S, Aubert H, Bodet D, Bourrat E, Chiaverini C, Poujade L, Willems M, Rouanet J, Dompmartin-Blanchère A, Geneviève D, Gerard M, Ginglinger E, Hadj-Rabia S, Martin L, Mazereeuw-Hautier J, Bibas N, Molinari N, Herman F, Phan A, Rod J, Roger H, Sigaudy S, Ziegler A, Vial Y, Verloes A, Cavé H, Lacombe D
J Eur Acad Dermatol Venereol 2024 Sep;38(9):1818-1827. Epub 2024 Apr 10 doi: 10.1111/jdv.19996. PMID: 38595321
Kenney-Jung DL, Collazo-Lopez JE, Rogers DJ, Shanley R, Zatkalik AL, Whitmarsh AE, Roberts AE, Zenker M, Pierpont EI
Am J Med Genet A 2024 Feb;194(2):301-310. Epub 2023 Oct 12 doi: 10.1002/ajmg.a.63428. PMID: 37827855Free PMC Article
Kenney-Jung DL, Rogers DJ, Kroening SJ, Zatkalik AL, Whitmarsh AE, Roberts AE, Zenker M, Gambardella ML, Contaldo I, Leoni C, Onesimo R, Zampino G, Tartaglia M, Battaglia DI, Pierpont EI
Am J Med Genet C Semin Med Genet 2022 Dec;190(4):501-509. Epub 2022 Nov 29 doi: 10.1002/ajmg.c.32022. PMID: 36448195Free PMC Article
Bessis D, Morice-Picard F, Bourrat E, Abadie C, Aouinti S, Baumann C, Best M, Bursztejn AC, Capri Y, Chiaverini C, Coubes C, Giuliano F, Hadj-Rabia S, Jacquemont ML, Lacombe D, Lyonnet S, Mallet S, Mazereeuw-Hautier J, Miquel J, Molinari N, Parfait B, Pernet C, Philip N, Pinson L, Pouvreau N, Vial Y, Sarda P, Sigaudy S, Verloes A, Cavé H, Geneviève D
Br J Dermatol 2019 Jan;180(1):172-180. Epub 2018 Sep 30 doi: 10.1111/bjd.17077. PMID: 30141192
Morton CM, Bhate C, Janniger CK, Schwartz RA
Cutis 2014 Feb;93(2):83-7. PMID: 24605344

Prognosis

Vaughn AR, Meyer SN, Nazir ZH, Tavernetti J, Simmons E, Li H, Rybak I, Rauen KA, Marghoob AA, Kiuru M
JAMA Dermatol 2024 Aug 1;160(8):869-873. doi: 10.1001/jamadermatol.2024.1697. PMID: 38888893Free PMC Article
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
Feng B, Li X, Zhang Q, Wang Y, Gu S, Yao RE, Li Z, Gao S, Chang G, Li Q, Li N, Fu L, Wang J, Wang X
Orphanet J Rare Dis 2023 Sep 11;18(1):284. doi: 10.1186/s13023-023-02878-0. PMID: 37697378Free PMC Article
Pierpont EI, Kenney-Jung DL, Shanley R, Zatkalik AL, Whitmarsh AE, Kroening SJ, Roberts AE, Zenker M
Genet Med 2022 Jul;24(7):1556-1566. Epub 2022 May 7 doi: 10.1016/j.gim.2022.04.004. PMID: 35524774
Abe Y, Aoki Y, Kuriyama S, Kawame H, Okamoto N, Kurosawa K, Ohashi H, Mizuno S, Ogata T, Kure S, Niihori T, Matsubara Y; Costello and CFC syndrome study group in Japan
Am J Med Genet A 2012 May;158A(5):1083-94. Epub 2012 Apr 11 doi: 10.1002/ajmg.a.35292. PMID: 22495831

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
Feng B, Li X, Zhang Q, Wang Y, Gu S, Yao RE, Li Z, Gao S, Chang G, Li Q, Li N, Fu L, Wang J, Wang X
Orphanet J Rare Dis 2023 Sep 11;18(1):284. doi: 10.1186/s13023-023-02878-0. PMID: 37697378Free PMC Article
Pierpont EI, Kenney-Jung DL, Shanley R, Zatkalik AL, Whitmarsh AE, Kroening SJ, Roberts AE, Zenker M
Genet Med 2022 Jul;24(7):1556-1566. Epub 2022 May 7 doi: 10.1016/j.gim.2022.04.004. PMID: 35524774
Jurcă MC, Iuhas OA, Puiu M, Chiriţă-Emandi A, Andreescu NI, Petcheşi CD, Jurcă AD, Magyar I, Jurcă SI, Kozma K, Severin EM, Bembea M
Rom J Morphol Embryol 2021 Apr-Jun;62(2):563-568. doi: 10.47162/RJME.62.2.23. PMID: 35024745Free PMC Article
Johnson B, Goldberg-Strassler D, Gripp K, Thacker M, Leoni C, Stevenson D
Am J Med Genet A 2015 Jan;167A(1):40-4. Epub 2014 Oct 24 doi: 10.1002/ajmg.a.36828. PMID: 25346259

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