Cardiofaciocutaneous syndrome

General Information (adopted from Orphanet):

Synonyms, Signs: CFC syndrome
Cardio-facio-cutaneous syndrome
Number of Symptoms 155
OrphanetNr: 1340
OMIM Id: 115150
615278
615279
615280
ICD-10: Q87.8
UMLs: C1275081
MeSH: C535579
MedDRA:
Snomed: 403770008

Prevalence, inheritance and age of onset:

Prevalence: 250 cases
Inheritance: Autosomal dominant
Sporadic
25487361 [IBIS]
Age of onset:

Disease classification (adopted from Orphanet):

Parent Diseases: Ectodermal dysplasia syndrome
 -Rare developmental defect during embryogenesis
 -Rare genetic disease
 -Rare skin disease
Multiple congenital anomalies/dysmorphic syndrome-intellectual deficit
 -Rare developmental defect during embryogenesis
 -Rare genetic disease
Noonan syndrome and Noonan-related syndrome
 -Rare cardiac disease
 -Rare developmental defect during embryogenesis
 -Rare genetic disease
Rare genetic intellectual deficit with developmental anomaly
 -Rare genetic disease
Rare intellectual deficit with developmental anomaly
 -Rare neurologic disease

Comment:

Cardiofaciocutaneous syndrome belongs to the group of RASopathies characterized by a distinctive facial appearance, congenital heart defects, ectodermal abnormalities and mental retardation. It overlaps phenotypically with Noonan and Costello syndrome, but can be differentiated from both diseases by the absence of arrhythmia. Skin findings such as ichthyosis, hyperkeratosis and keratosis pilaris are more characteristic of CFC than of Costello or Noonan syndromes, and may also help to distinguish them. (PMID:18039946)

Symptom Information: Sort by abundance 

1
(HPO:0003270) Abdominal distention Frequent [IBIS] 38% (n=32) 18039946 IBIS 46 / 7739
2
(HPO:0002019) Constipation 15490149 IBIS 194 / 7739
3
(HPO:0011968) Feeding difficulties Frequent [IBIS] 56% (n=35) 18039946 IBIS 240 / 7739
4
(HPO:0008872) Feeding difficulties in infancy 15490149 IBIS 153 / 7739
5
(HPO:0002013) Vomiting Frequent [IBIS] 57% (n=37) 18039946 IBIS 191 / 7739
6
(HPO:0004396) Poor appetite Frequent [IBIS] 60% (n=35) 18039946 IBIS 7 / 7739
7
(HPO:0000316) Hypertelorism Frequent [Orphanet] 25180280 IBIS 644 / 7739
8
(HPO:0000520) Proptosis 18039946 IBIS 192 / 7739
9
(HPO:0000587) Abnormality of the optic nerve Frequent [IBIS] 42% (n=26) 18039946 IBIS 5 / 7739
10
(HPO:0001093) Optic nerve dysplasia 25180280 IBIS 6 / 7739
11
(HPO:0000639) Nystagmus Frequent [Orphanet] 25180280 IBIS 555 / 7739
12
(HPO:0000486) Strabismus Frequent [IBIS] Frequent [Orphanet] 80% (n=35) 18039946 IBIS 576 / 7739
13
(HPO:0000539) Abnormality of refraction Frequent [IBIS] 71% (n=28) 18039946 IBIS 6 / 7739
14
(HPO:0000545) Myopia Frequent [IBIS] Frequent [Orphanet] 18039946 IBIS 286 / 7739
15
(HPO:0000508) Ptosis Frequent [Orphanet] 25180280 IBIS 459 / 7739
16
(HPO:0002202) Pleural effusion Rare [IBIS] 3% (n=38) 18039946 IBIS 22 / 7739
17
(HPO:0008751) Laryngeal cleft 25180280 IBIS 5 / 7739
18
(HPO:0004322) Short stature Frequent [IBIS] Very frequent [Orphanet] 71% (n=38) 18039946 IBIS 1232 / 7739
19
(HPO:0004325) Decreased body weight Very frequent [Orphanet] 24637312 IBIS 492 / 7739
20
(HPO:0001508) Failure to thrive Frequent [IBIS] 67% (n=36) 18039946 IBIS 454 / 7739
21
(HPO:0001520) Large for gestational age Occasional [IBIS] 16% (n=69) 26494162 IBIS 34 / 7739
22
(HPO:0001631) Atria septal defect Occasional [IBIS] Very frequent [Orphanet] 28% (n=33) 18039946 IBIS 274 / 7739
23
(HPO:0001682) Subaortic stenosis Occasional [IBIS] 15% (n=33) 18039946 IBIS 17 / 7739
24
(HPO:0001629) Ventricular septal defect Occasional [IBIS] 22% (n=33) 18039946 IBIS 316 / 7739
25
(HPO:0001633) Abnormality of the mitral valve Occasional [IBIS] 18039946 IBIS 69 / 7739
26
(HPO:0001702) Abnormality of the tricuspid valve Rare [IBIS] 18039946 IBIS 32 / 7739
27
(HPO:0001646) Abnormality of the aortic valve Rare [IBIS] 3% (n=33) 18039946 IBIS 55 / 7739
28
(HPO:0001637) Abnormality of the myocardium 23950000 IBIS 76 / 7739
29
(HPO:0001638) Cardiomyopathy Occasional [Orphanet] 25827862 IBIS 192 / 7739
30
(HPO:0001639) Hypertrophic cardiomyopathy Frequent [IBIS] 39% (n=33) 18039946 IBIS 137 / 7739
31
(HPO:0002119) Ventriculomegaly 18039946 IBIS 253 / 7739
32
(HPO:0001680) Coarctation of aorta Rare [IBIS] 6% (n=33) 18039946 IBIS 57 / 7739
33
(HPO:0001642) Pulmonic stenosis Frequent [IBIS] 42% (n=33) 18039946 IBIS 89 / 7739
34
(HPO:0000824) Growth hormone deficiency Rare [IBIS] 5% (n=38) 18039946 IBIS 56 / 7739
35
(HPO:0001004) Lymphedema Occasional [IBIS] Occasional [Orphanet] 26242988 IBIS 62 / 7739
36
(HPO:0001252) Muscular hypotonia Very frequent [IBIS] Very frequent [Orphanet] 94% (n=36) 18039946 IBIS 990 / 7739
37
(HPO:0003477) Peripheral axonal neuropathy Rare [IBIS] rare [HPO:skoehler] 17437909 IBIS 62 / 7739
38
(HPO:0001251) Ataxia Occasional [IBIS] 18039946 IBIS 413 / 7739
39
(HPO:0001269) Hemiparesis Rare [IBIS] 18039946 IBIS 51 / 7739
40
(HPO:0000708) Behavioral abnormality Frequent [IBIS] 18039946 IBIS 212 / 7739
41
(HPO:0000718) Aggressive behavior Occasional [IBIS] 27% (n=34) 18039946 IBIS 109 / 7739
42
(HPO:0001263) Global developmental delay Very frequent [IBIS] 18039946 IBIS 853 / 7739
43
(HPO:0001249) Intellectual disability Very frequent [IBIS] 100% (n=27) 18039946 IBIS 1089 / 7739
44
(HPO:0002194) Delayed gross motor development Very frequent [IBIS] 18039946 IBIS 37 / 7739
45
(HPO:0000737) Irritability Frequent [IBIS] 52% (n=33) 18039946 IBIS 93 / 7739
46
(HPO:0000722) Obsessive-compulsive behavior Frequent [IBIS] 41% (n=32) 18039946 IBIS 35 / 7739
47
(MedDRA:10065954) Stubbornness Frequent [IBIS] 48% (n=31) 18039946 IBIS 5 / 7739
48
(HPO:0000736) Short attention span Frequent [IBIS] 70% (n=33) 18039946 IBIS 16 / 7739
49
(HPO:0002360) Sleep disturbance Frequent [IBIS] 18039946 IBIS 113 / 7739
50
(HPO:0010535) Sleep apnea Occasional [IBIS] 22% (n=36) 18039946 IBIS 24 / 7739
51
(HPO:0100703) Tongue thrusting Occasional [IBIS] 18039946 IBIS 4 / 7739
52
(HPO:0002015) Dysphagia Frequent [IBIS] 64% (n=31) 18039946 IBIS 301 / 7739
53
(HPO:0001250) Seizures Frequent [IBIS] 49% (n=37) 18039946 IBIS 1245 / 7739
54
(HPO:0012469) Infantile spasms Occasional [IBIS] 18039946 IBIS 18 / 7739
55
(HPO:0001561) Polyhydramnios Frequent [IBIS] 52% (n=69) 26494162 IBIS 191 / 7739
56
(HPO:0002967) Cubitus valgus Occasional [Orphanet] 20523244 IBIS 49 / 7739
57
(HPO:0000347) Micrognathia 25827862 IBIS 426 / 7739
58
(HPO:0000268) Dolichocephaly 25180280 IBIS 144 / 7739
59
(HPO:0002007) Frontal bossing Frequent [Orphanet] 23950000 IBIS 366 / 7739
60
(HPO:0000348) High forehead Frequent [Orphanet] 25180280 IBIS 157 / 7739
61
(HPO:0000256) Macrocephaly Frequent [IBIS] Frequent [Orphanet] 64% (n=33) 18039946 IBIS 298 / 7739
62
(HPO:0000341) Narrow forehead Frequent [Orphanet] 25180280 IBIS 96 / 7739
63
(HPO:0011220) Prominent forehead 1915501 IBIS 137 / 7739
64
(HPO:0004482) Relative macrocephaly Frequent [IBIS] 52% (n=33) 18039946 IBIS 44 / 7739
65
(HPO:0000766) Abnormality of the sternum Frequent [IBIS] 63% (n=29) 18039946 IBIS 31 / 7739
66
(HPO:0000768) Pectus carinatum Frequent [IBIS] 18039946 IBIS 136 / 7739
67
(HPO:0000767) Pectus excavatum Frequent [IBIS] Frequent [Orphanet] 18039946 IBIS 244 / 7739
68
(HPO:0000470) Short neck Frequent [Orphanet] 25827862 IBIS 345 / 7739
69
(HPO:0002808) Kyphosis Occasional [IBIS] 23% (n=26) 18039946 IBIS 289 / 7739
70
(HPO:0002650) Scoliosis Frequent [IBIS] Frequent [Orphanet] 33% (n=33) 18039946 IBIS 705 / 7739
71
(HPO:0007370) Aplasia/Hypoplasia of the corpus callosum 20395089 IBIS 180 / 7739
72
(HPO:0001382) Joint hypermobility Frequent [IBIS] 63% (n=27) 18039946 IBIS 231 / 7739
73
(HPO:0002750) Delayed skeletal maturation Frequent [IBIS] 33% (n=38) 18039946 IBIS 250 / 7739
74
(HPO:0010720) Abnormal hair pattern Very requent [IBIS] Very frequent [Orphanet] 18039946 IBIS 14 / 7739
75
(HPO:0002223) Absent eyebrow 18039946 IBIS 21 / 7739
76
(HPO:0000561) Absent eyelashes 16361753; 26494162 IBIS 18 / 7739
77
(HPO:0000653) Sparse eyelashes Rare [IBIS] 5% (n=38) 18039946 IBIS 58 / 7739
78
(HPO:0008070) Sparse hair Frequent [IBIS] 84% (n=38) 18039946 IBIS 94 / 7739
79
(HPO:0010719) Abnormality of hair texture Frequent [IBIS] 18039946 IBIS 24 / 7739
80
(HPO:0002299) Brittle hair Very frequent [Orphanet] 18039946 IBIS 52 / 7739
81
(HPO:0002212) Curly hair Very frequent [IBIS] 92% (n=38) 18039946 IBIS 21 / 7739
82
(HPO:0100840) Aplasia/Hypoplasia of the eyebrow Frequent [IBIS] Very frequent [Orphanet] 86% (n=35) 18039946 IBIS 117 / 7739
83
(HPO:0009553) Abnormality of the hairline Occasional [IBIS] 8% (n=38) 18039946 IBIS 30 / 7739
84
(HPO:0002293) Alopecia of scalp 16361753 IBIS 9 / 7739
85
(HPO:0001006) Hypotrichosis Frequent [Orphanet] 8867661 IBIS 219 / 7739
86
(HPO:0001597) Abnormality of the nail Occasional [IBIS] 16% (n=38) 18039946 IBIS 115 / 7739
87
(HPO:0008404) Nail dystrophy 15186229 IBIS 89 / 7739
88
(HPO:0002020) Gastroesophageal reflux Frequent [IBIS] 55% (n=38) 18039946 IBIS 101 / 7739
89
(HPO:0002579) Gastrointestinal dysmotility Frequent [IBIS] 18039946 IBIS 11 / 7739
90
(HPO:0002240) Hepatomegaly Occasional [IBIS] 8% (n=38) 18039946 IBIS 467 / 7739
91
(HPO:0001744) Splenomegaly 2596506 IBIS 337 / 7739
92
(HPO:0001537) Umbilical hernia Occasional [IBIS] 16% (n=32) 18039946 IBIS 206 / 7739
93
(HPO:0000023) Inguinal hernia Rare [IBIS] 6% (n=33) 18039946 IBIS 181 / 7739
94
(HPO:0001626) Abnormality of the cardiovascular system Frequent [IBIS] 71% (n=38) 18039946 IBIS 73 / 7739
95
(HPO:0000478) Abnormality of the eye Very frequent [IBIS] Very frequent [Orphanet] 25180280 IBIS 126 / 7739
96
(HPO:0000028) Cryptorchidism Frequent [IBIS] 38% (n=16) 18039946 IBIS 347 / 7739
97
(HPO:0000035) Abnormality of the testis Frequent [IBIS] Frequent [Orphanet] 18039946 IBIS 296 / 7739
98
(HPO:0000119) Abnormality of the genitourinary system Frequent [IBIS] 18039946 IBIS 34 / 7739
99
(HPO:0000280) Coarse facial features Very frequent [IBIS] Very frequent [Orphanet] 25180280 IBIS 189 / 7739
100
(HPO:0000689) Dental malocclusion 22946697 IBIS 114 / 7739
101
(HPO:0000494) Downslanted palpebral fissures Frequent [Orphanet] 25180280 IBIS 328 / 7739
102
(HPO:0010807) Open bite 25180280 IBIS 6 / 7739
103
(HPO:0009891) Underdeveloped supraorbital ridges Very frequent [Orphanet] 25180280 IBIS 36 / 7739
104
(HPO:0000174) Abnormality of the palate Occasional [Orphanet] 25180280 IBIS 298 / 7739
105
(HPO:0000218) High palate 25180280 IBIS 356 / 7739
106
(HPO:0002705) High, narrow palate Frequent [Orphanet] 25180280 IBIS 308 / 7739
107
(HPO:0002002) Deep philtrum 25180280 IBIS 42 / 7739
108
(HPO:0000194) Open mouth 25180280 IBIS 70 / 7739
109
(HPO:0000463) Anteverted nares Very frequent [Orphanet] 25180280 IBIS 305 / 7739
110
(HPO:0000414) Bulbous nose 25180280 IBIS 63 / 7739
111
(HPO:0005280) Depressed nasal bridge Frequent [Orphanet] 16361753 IBIS 381 / 7739
112
(HPO:0003196) Short nose Frequent [IBIS] Frequent [Orphanet] 25180280 IBIS 264 / 7739
113
(HPO:0000286) Epicanthus Frequent [Orphanet] 25180280 IBIS 371 / 7739
114
(HPO:0000389) Chronic otitis media Frequent [IBIS] 55% (n=31) 18039946 IBIS 64 / 7739
115
(HPO:0000465) Webbed neck Frequent [Orphanet] 20523244 IBIS 81 / 7739
116
(HPO:0000357) Abnormal location of ears Frequent [IBIS] Frequent [Orphanet] 25180280 IBIS 328 / 7739
117
(HPO:0000372) Abnormality of the auditory canal Frequent [IBIS] 18039946 IBIS 49 / 7739
118
(HPO:0009908) Anterior creases of earlobe 25180280 IBIS 10 / 7739
119
(HPO:0000369) Low-set ears 25180280 IBIS 372 / 7739
120
(HPO:0000358) Posteriorly rotated ears 25180280 IBIS 163 / 7739
121
(HPO:0000957) Cafe-au-lait spot Occasional [IBIS] Frequent [Orphanet] 27% (n=33) 18039946 IBIS 84 / 7739
122
(HPO:0000953) Hyperpigmentation of the skin Frequent [Orphanet] 25180280 IBIS 75 / 7739
123
(HPO:0003764) Nevus Frequent [IBIS] 76% (n=37) 18039946 IBIS 17 / 7739
124
(HPO:0000958) Dry skin Very frequent [Orphanet] 25180280 IBIS 152 / 7739
125
(HPO:0000962) Hyperkeratosis Frequent [IBIS] Frequent [Orphanet] 61% (n=28) 18039946 IBIS 216 / 7739
126
(HPO:0008064) Ichthyosis Occasional [IBIS] Frequent [Orphanet] 30% (n=27) 18039946 IBIS 108 / 7739
127
(HPO:0001047) Atopic dermatitis Occasional [IBIS] 27% (n=26) 18039946 IBIS 20 / 7739
128
(HPO:0001028) Hemangioma Frequent [IBIS] 47% (n=32) 18039946 IBIS 23 / 7739
129
(HPO:0001048) Cavernous hemangioma 17551339 IBIS 28 / 7739
130
(HPO:0100678) Premature skin wrinkling Very frequent [Orphanet] 8867661 IBIS 25 / 7739
131
(HPO:0000989) Pruritus Frequent [IBIS] 44% (n=34) 18039946 IBIS 111 / 7739
132
(HPO:0000076) Vesicoureteral reflux 18039946 IBIS 94 / 7739
133
(HPO:0000077) Abnormality of the kidney 18039946 IBIS 73 / 7739
134
(HPO:0000126) Hydronephrosis Rare [IBIS] 5% (n=38) 18039946 IBIS 119 / 7739
135
(HPO:0000105) Enlarged kidneys Occasional [IBIS] 18039946 IBIS 30 / 7739
136
(HPO:0000072) Hydroureter Occasional [Orphanet] 18039946 IBIS 146 / 7739
137
(HPO:0004414) Abnormality of the pulmonary artery Very frequent [Orphanet] 23950000 IBIS 50 / 7739
138
(HPO:0000365) Hearing impairment 25180280 IBIS 539 / 7739
139
(HPO:0012192) Cutaneous T-cell lymphoma Rare [IBIS] 6% (n=34) 18039946 IBIS 1 / 7739
140
(HPO:0010880) Increased nuchal translucency Occasional [IBIS] 13% (n=69) 26494162 IBIS 13 / 7739
141
(HPO:0001622) Premature birth Frequent [IBIS] Frequent [Orphanet] 49% (n=38) 18039946 IBIS 100 / 7739
142
(HPO:0008373) Puberty and gonadal disorders Occasional [Orphanet] 18039946 IBIS 156 / 7739
143
(HPO:0002500) Abnormality of the cerebral white matter Occasional [IBIS] 26% (n=23) 18039946 IBIS 73 / 7739
144
(HPO:0012795) Abnormality of the optic disc Occasional [Orphanet] 8911596 IBIS 187 / 7739
145
(HPO:0007099) Arnold-Chiari type I malformation Rare [IBIS] 4% (n=23) 18039946 IBIS 18 / 7739
146
(HPO:0002059) Cerebral atrophy Occasional [IBIS] 13% (n=23) 18039946 IBIS 171 / 7739
147
(HPO:0002188) Delayed CNS myelination Occasional [IBIS] 13% (n=23) 18039946 IBIS 16 / 7739
148
(HPO:0012719) Functional abnormality of the gastrointestinal tract Occasional [Orphanet] 15490149 IBIS 17 / 7739
149
(HPO:0000238) Hydrocephalus Occasional [IBIS] Occasional [Orphanet] 22% (n=32) 18039946 IBIS 278 / 7739
150
(HPO:0040180) Hyperkeratosis pilaris Frequent [IBIS] 73% (n=26) 18039946 IBIS 3 / 7739
151
(HPO:0030215) Inappropriate crying Frequent [IBIS] 50% (n=36) 18039946 IBIS 1 / 7739
152
(HPO:0012718) Morphological abnormality of the gastrointestinal tract Occasional [Orphanet] 15490149 IBIS 5 / 7739
153
(HPO:0012758) Neurodevelopmental delay Very frequent [IBIS] Very frequent [Orphanet] 25180280 IBIS 949 / 7739
154
(MedDRA:10064195) Right ventricle outflow tract obstruction Rare [IBIS] 18039946 IBIS 4 / 7739
155
(OMIM) Small external auditory canals Frequent [IBIS] 79% (n=29) 18039946 IBIS 2 / 7739

Associated genes:

BRAF; KRAS; MAP2K1; MAP2K2;

ClinVar (via SNiPA)

Gene symbol Variation Clinical significance Reference
BRAF rs121913341 likely pathogenic RCV000154266.1
BRAF rs121913348 likely pathogenic RCV000150212.1
BRAF rs121913355 pathogenic RCV000015008.28
BRAF rs121913369 pathogenic RCV000154400.1
BRAF rs180177034 pathogenic RCV000014998.26
BRAF rs180177035 pathogenic RCV000015007.28
BRAF rs180177036 pathogenic RCV000154481.1
BRAF rs180177036 pathogenic RCV000015009.28
BRAF rs180177037 pathogenic RCV000015010.26
BRAF rs180177038 likely pathogenic RCV000037923.2
BRAF rs180177038 pathogenic RCV000015011.28
BRAF rs180177039 likely pathogenic RCV000037924.2
BRAF rs180177039 pathogenic RCV000015012.25
BRAF rs180177040 pathogenic RCV000015013.28
BRAF rs180177041 pathogenic RCV000015014.27
BRAF rs180177042 pathogenic RCV000150199.1
BRAF rs180177042 pathogenic RCV000015015.27
BRAF rs387906661 pathogenic RCV000022680.27
BRAF rs397507465 pathogenic RCV000037955.2
BRAF rs397507466 likely pathogenic RCV000037957.2
BRAF rs397507466 likely pathogenic RCV000037956.2
BRAF rs397507469 likely pathogenic RCV000037959.2
BRAF rs397507473 pathogenic RCV000037917.2
BRAF rs397507474 likely pathogenic RCV000150208.1
BRAF rs397507475 likely pathogenic RCV000150207.1
BRAF rs397507480 likely pathogenic RCV000037927.2
BRAF rs397507483 pathogenic RCV000150204.1
BRAF rs397516892 likely pathogenic RCV000037921.2
BRAF rs397516893 likely pathogenic RCV000037922.2
BRAF rs397516894 pathogenic RCV000037928.2
BRAF rs397516895 pathogenic RCV000037929.2
BRAF rs397516904 likely pathogenic RCV000037960.2
BRAF rs794729219 pathogenic RCV000184039.1
MAP2K2 rs730880517 likely pathogenic RCV000200295.1

Additional Information:

Diagnosis GeneReviews Cardiofaciocutaneous (CFC) syndrome is one the RASopathies: a group of syndromes having overlapping clinical features resulting from a common pathogenetic mechanism [Tidyman & Rauen 2009a]....
Clinical Description GeneReviews Cardiofaciocutaneous (CFC) syndrome affects males and females equally. ...
Genotype-Phenotype Correlations GeneReviews Further evaluation of more individuals with CFC syndrome is necessary to clarify genotype-phenotype correlations, thereby permitting more accurate prognoses. ...
Differential Diagnosis GeneReviews Multi-gene panels may include testing for a number of the genes associated with disorders discussed in this section. ...
Management GeneReviews The following evaluations are recommended in an individual known to have or suspected to have cardiofaciocutaneous (CFC) syndrome:...
Molecular genetics GeneReviews Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED....