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Cardiofaciocutaneous syndrome 3(CFC3)

MedGen UID:
815336
Concept ID:
C3809006
Disease or Syndrome
Synonyms: CFC3; MAP2K1-Related Cardiofaciocutaneous Syndrome
 
Gene (location): MAP2K1 (15q22.31)
 
Monarch Initiative: MONDO:0014113
OMIM®: 615279

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 syndrome (CFC) is a complex developmental disorder involving characteristic craniofacial features, cardiac anomalies, hair and skin abnormalities, postnatal growth deficiency, hypotonia, and developmental delay. Distinctive features of CFC3 include macrostomia and horizontal shape of palpebral fissures (Schulz et al., 2008). For a general description and a discussion of genetic heterogeneity of cardiofaciocutaneous syndrome, see CFC1 (115150).  http://www.omim.org/entry/615279

Clinical features

From HPO
Hypertrophic cardiomyopathy
MedGen UID:
2881
Concept ID:
C0007194
Disease or Syndrome
Hypertrophic cardiomyopathy (HCM) is defined by the presence of increased ventricular wall thickness or mass in the absence of loading conditions (hypertension, valve disease) sufficient to cause the observed abnormality.
Atrial septal defect
MedGen UID:
6753
Concept ID:
C0018817
Congenital Abnormality
Atrial septal defect (ASD) is a congenital abnormality of the interatrial septum that enables blood flow between the left and right atria via the interatrial septum.
Ventricular septal defect
MedGen UID:
42366
Concept ID:
C0018818
Congenital Abnormality
A hole between the two bottom chambers (ventricles) of the heart. The defect is centered around the most superior aspect of the ventricular septum.
Pulmonic stenosis
MedGen UID:
408291
Concept ID:
C1956257
Disease or Syndrome
A narrowing of the right ventricular outflow tract that can occur at the pulmonary valve (valvular stenosis), below the pulmonary valve (infundibular stenosis), or above the pulmonary valve (supravalvar stenosis).
Short stature
MedGen UID:
87607
Concept ID:
C0349588
Finding
A height below that which is expected according to age and gender norms. Although there is no universally accepted definition of short stature, many refer to "short stature" as height more than 2 standard deviations below the mean for age and gender (or below the 3rd percentile for age and gender dependent norms).
Failure to thrive
MedGen UID:
746019
Concept ID:
C2315100
Disease or Syndrome
Failure to thrive (FTT) refers to a child whose physical growth is substantially below the norm.
Seizure
MedGen UID:
20693
Concept ID:
C0036572
Sign or Symptom
A seizure is an intermittent abnormality of nervous system physiology characterised by a transient occurrence of signs and/or symptoms due to abnormal excessive or synchronous neuronal activity in the brain.
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.
Intellectual disability
MedGen UID:
811461
Concept ID:
C3714756
Mental or Behavioral Dysfunction
Intellectual disability, previously referred to as mental retardation, is characterized by subnormal intellectual functioning that occurs during the developmental period. It is defined by an IQ score below 70.
Hypotonia
MedGen UID:
10133
Concept ID:
C0026827
Finding
Hypotonia is an abnormally low muscle tone (the amount of tension or resistance to movement in a muscle). Even when relaxed, muscles have a continuous and passive partial contraction which provides some resistance to passive stretching. Hypotonia thus manifests as diminished resistance to passive stretching. Hypotonia is not the same as muscle weakness, although the two conditions can co-exist.
Scoliosis
MedGen UID:
11348
Concept ID:
C0036439
Disease or Syndrome
The presence of an abnormal lateral curvature of the spine.
Pectus excavatum
MedGen UID:
781174
Concept ID:
C2051831
Finding
A defect of the chest wall characterized by a depression of the sternum, giving the chest ("pectus") a caved-in ("excavatum") appearance.
Reduced bone mineral density
MedGen UID:
393152
Concept ID:
C2674432
Finding
A reduction of bone mineral density, that is, of the amount of matter per cubic centimeter of bones.
Heat intolerance
MedGen UID:
66659
Concept ID:
C0231274
Pathologic Function
The inability to maintain a comfortable body temperature in warm or hot weather.
Wide mouth
MedGen UID:
44238
Concept ID:
C0024433
Congenital Abnormality
Distance between the oral commissures more than 2 SD above the mean. Alternatively, an apparently increased width of the oral aperture (subjective).
Webbed neck
MedGen UID:
113154
Concept ID:
C0221217
Congenital Abnormality
Pterygium colli is a congenital skin fold that runs along the sides of the neck down to the shoulders. It involves an ectopic fibrotic facial band superficial to the trapezius muscle. Excess hair-bearing skin is also present and extends down the cervical region well beyond the normal hairline.
Short neck
MedGen UID:
99267
Concept ID:
C0521525
Finding
Diminished length of the neck.
Hyperhidrosis
MedGen UID:
5690
Concept ID:
C0020458
Finding
Abnormal excessive perspiration (sweating) despite the lack of appropriate stimuli like hot and humid weather.
Keratosis pilaris
MedGen UID:
82664
Concept ID:
C0263383
Disease or Syndrome
An anomaly of the hair follicles of the skin that typically presents as small, rough, brown folliculocentric papules distributed over characteristic areas of the skin, particularly the outer-upper arms and thighs.
Curly hair
MedGen UID:
488919
Concept ID:
C0558165
Finding
Hyperkeratosis
MedGen UID:
209030
Concept ID:
C0870082
Disease or Syndrome
Hyperkeratosis is thickening of the outer layer of the skin, the stratum corneum, which is composed of large, polyhedral, plate-like envelopes filled with keratin which are the dead cells that have migrated up from the stratum granulosum.
Nystagmus
MedGen UID:
45166
Concept ID:
C0028738
Disease or Syndrome
Rhythmic, involuntary oscillations of one or both eyes related to abnormality in fixation, conjugate gaze, or vestibular mechanisms.

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
Čizmárová M, Hlinková K, Bertok S, Kotnik P, Duba HC, Bertalan R, Poločková K, Košťálová Ľ, Pribilincová Z, Hlavatá A, Kovács L, Ilenčíková D
Ann Hum Genet 2016 Jan;80(1):50-62. Epub 2015 Nov 26 doi: 10.1111/ahg.12140. PMID: 26607044

Recent clinical studies

Etiology

Jelin AC, Mahle A, Tran SH, Sparks TN, Rauen KA
Am J Med Genet A 2023 Feb;191(2):323-331. Epub 2022 Oct 29 doi: 10.1002/ajmg.a.63020. PMID: 36308388Free PMC Article
Siano MA, Pivonello R, Salerno M, Falco M, Mauro C, De Brasi D, Klain A, Sestito S, De Luca A, Pinna V, Simeoli C, Concolino D, Mainolfi CG, Mannarino T, Strisciuglio P, Tartaglia M, Melis D
Front Endocrinol (Lausanne) 2022;13:1030398. Epub 2022 Nov 18 doi: 10.3389/fendo.2022.1030398. PMID: 36483002Free PMC Article
Karaer K, Lissewski C, Zenker M
Am J Med Genet A 2015 Feb;167A(2):385-8. Epub 2014 Dec 8 doi: 10.1002/ajmg.a.36429. PMID: 25487361
Pierpont EI, Pierpont ME, Mendelsohn NJ, Roberts AE, Tworog-Dube E, Rauen KA, Seidenberg MS
Am J Med Genet A 2010 Mar;152A(3):591-600. doi: 10.1002/ajmg.a.33268. PMID: 20186801Free PMC Article
Weiss G, Confino Y, Shemer A, Trau H
J Eur Acad Dermatol Venereol 2004 May;18(3):324-7. doi: 10.1111/j.1468-3083.2004.00365.x. PMID: 15096145

Diagnosis

Lallar M, Bijarnia-Mahay S, Verma IC, Mandal K, Puri RD
Indian Pediatr 2021 Jan 15;58(1):30-33. PMID: 33452774
Mangels R, Blumenfeld YJ, Homeyer M, Mrazek-Pugh B, Hintz SR, Hudgins L
Prenat Diagn 2021 Feb;41(3):362-367. Epub 2020 Nov 18 doi: 10.1002/pd.5862. PMID: 33150592
Lee Y, Choi Y, Seo GH, Kim GH, Choi IH, Keum C, Ko JM, Cheon CK, Jeon J, Choi JH, Yoo HW, Lee BH
J Hum Genet 2021 Apr;66(4):389-399. Epub 2020 Oct 10 doi: 10.1038/s10038-020-00852-3. PMID: 33040082
Karaer K, Lissewski C, Zenker M
Am J Med Genet A 2015 Feb;167A(2):385-8. Epub 2014 Dec 8 doi: 10.1002/ajmg.a.36429. PMID: 25487361
Weiss G, Confino Y, Shemer A, Trau H
J Eur Acad Dermatol Venereol 2004 May;18(3):324-7. doi: 10.1111/j.1468-3083.2004.00365.x. PMID: 15096145

Therapy

Jeffries ML, Aleck KA, Bernert RA, Hansen RC
Pediatr Dermatol 2010 May-Jun;27(3):274-8. Epub 2009 Oct 4 doi: 10.1111/j.1525-1470.2009.00982.x. PMID: 19804494

Prognosis

Jelin AC, Mahle A, Tran SH, Sparks TN, Rauen KA
Am J Med Genet A 2023 Feb;191(2):323-331. Epub 2022 Oct 29 doi: 10.1002/ajmg.a.63020. PMID: 36308388Free PMC Article
Çelik N, Cinaz P, Bideci A, Yüce Ö, Emeksiz HC, Döğer E, Çamurdan O
J Clin Res Pediatr Endocrinol 2014;6(1):55-8. doi: 10.4274/Jcrpe.1151. PMID: 24637312Free PMC Article
Reinker KA, Stevenson DA, Tsung A
J Pediatr Orthop 2011 Jul-Aug;31(5):599-605. doi: 10.1097/BPO.0b013e318220396e. PMID: 21654472
Pierpont EI, Pierpont ME, Mendelsohn NJ, Roberts AE, Tworog-Dube E, Rauen KA, Seidenberg MS
Am J Med Genet A 2010 Mar;152A(3):591-600. doi: 10.1002/ajmg.a.33268. PMID: 20186801Free PMC Article
Weiss G, Confino Y, Shemer A, Trau H
J Eur Acad Dermatol Venereol 2004 May;18(3):324-7. doi: 10.1111/j.1468-3083.2004.00365.x. PMID: 15096145

Clinical prediction guides

Siano MA, Pivonello R, Salerno M, Falco M, Mauro C, De Brasi D, Klain A, Sestito S, De Luca A, Pinna V, Simeoli C, Concolino D, Mainolfi CG, Mannarino T, Strisciuglio P, Tartaglia M, Melis D
Front Endocrinol (Lausanne) 2022;13:1030398. Epub 2022 Nov 18 doi: 10.3389/fendo.2022.1030398. PMID: 36483002Free PMC Article
Inoue SI, Morozumi N, Yoshikiyo K, Maeda H, Aoki Y
Hum Mol Genet 2019 Jan 1;28(1):74-83. doi: 10.1093/hmg/ddy333. PMID: 30239744
Karaer K, Lissewski C, Zenker M
Am J Med Genet A 2015 Feb;167A(2):385-8. Epub 2014 Dec 8 doi: 10.1002/ajmg.a.36429. PMID: 25487361
Krejci P
Mutat Res Rev Mutat Res 2014 Jan-Mar;759:40-8. Epub 2013 Dec 1 doi: 10.1016/j.mrrev.2013.11.001. PMID: 24295726
Siegel DH, Mann JA, Krol AL, Rauen KA
Br J Dermatol 2012 Mar;166(3):601-7. doi: 10.1111/j.1365-2133.2011.10744.x. PMID: 22098123Free PMC Article

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