Costello syndrome

General Information (adopted from Orphanet):

Synonyms, Signs: FCS SYNDROME MYOPATHY, CONGENITAL, WITH EXCESS OF MUSCLE SPINDLES, INCLUDED
CMEMS, INCLUDED
faciocutaneoskeletal syndrome
Intellectual deficit - nasal papillomata
FCS syndrome
Number of Symptoms 133
OrphanetNr: 3071
OMIM Id: 218040
ICD-10: Q87.8
UMLs: C0587248
MeSH: D056685
MedDRA: 10067380
Snomed: 309776008

Prevalence, inheritance and age of onset:

Prevalence: 300 cases - PMID: 24902452 [IBIS]
Inheritance: Autosomal dominant
- PMID: 25133308 [IBIS]
Age of onset:

Disease classification (adopted from Orphanet):

Parent Diseases: Genetic dermis elastic tissue disorder
 -Rare genetic disease
 -Rare skin disease
Malformation syndrome with skin/mucosae involvement
 -Rare developmental defect during embryogenesis
 -Rare genetic 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
Polymalformative genetic syndrome with increased risk of developing cancer
 -Rare genetic disease
 -Rare oncologic disease
Rare genetic intellectual deficit with developmental anomaly
 -Rare genetic disease
Rare intellectual deficit with developmental anomaly
 -Rare neurologic disease

Comment:

Costello syndrome belongs to the group of RASopathies and is caused by activating mutations in the proto-oncogene HRAS, a key regulator of the MAPK pathway (PMID:21495179). Individuals with HRAS-p.G12A or -p.G12C mutation are more severely affected than those with other HRAS mutations (PMID:23429430).

Symptom Information: Sort by abundance 

1
(HPO:0011968) Feeding difficulties 23429430 IBIS 240 / 7739
2
(HPO:0000483) Astigmatism 15940703 IBIS 67 / 7739
3
(HPO:0100692) Increased corneal curvature Frequent [Orphanet] 23494969 IBIS 13 / 7739
4
(HPO:0000639) Nystagmus Frequent [IBIS] 42% (n=33) 16329078 IBIS 555 / 7739
5
(HPO:0000486) Strabismus Frequent [Orphanet] 21438134 IBIS 576 / 7739
6
(HPO:0000540) Hypermetropia 21438134 IBIS 99 / 7739
7
(HPO:0012471) Thick vermilion border Frequent [Orphanet] 21438134; 19288554 IBIS 115 / 7739
8
(HPO:0000545) Myopia 15940703 IBIS 286 / 7739
9
(HPO:0000508) Ptosis 21438134 IBIS 459 / 7739
10
(HPO:0002202) Pleural effusion 21438134 IBIS 22 / 7739
11
(HPO:0002093) Respiratory insufficiency 22926243 IBIS 410 / 7739
12
(HPO:0001609) Hoarse voice 9934987 IBIS 34 / 7739
13
(HPO:0001601) Laryngomalacia 21438134 IBIS 61 / 7739
14
(HPO:0004322) Short stature Very frequent [IBIS] Very frequent [Orphanet] 21438134 IBIS 1232 / 7739
15
(HPO:0004325) Decreased body weight Very frequent [Orphanet] 19288554 IBIS 492 / 7739
16
(HPO:0001508) Failure to thrive Very frequent [IBIS] 23429430 IBIS 454 / 7739
17
(HPO:0001531) Failure to thrive in infancy Very frequent [IBIS] 100% (n=40) 16329078 IBIS 26 / 7739
18
(HPO:0001520) Large for gestational age Frequent [IBIS] 17726614 IBIS 34 / 7739
19
(HPO:0001943) Hypoglycemia 21438134 IBIS 131 / 7739
20
(HPO:0001998) Neonatal hypoglycemia 21438134 IBIS 22 / 7739
21
(HPO:0001631) Atria septal defect 17726614 IBIS 274 / 7739
22
(HPO:0001629) Ventricular septal defect Very frequent [Orphanet] 17726614 IBIS 316 / 7739
23
(HPO:0001633) Abnormality of the mitral valve Frequent [Orphanet] 17726614 IBIS 69 / 7739
24
(HPO:0001634) Mitral valve prolapse 17726614 IBIS 69 / 7739
25
(HPO:0005180) Tricuspid regurgitation 15940703 IBIS 20 / 7739
26
(HPO:0001641) Abnormality of the pulmonary valve Very frequent [Orphanet] 21438134 IBIS 27 / 7739
27
(HPO:0001638) Cardiomyopathy Frequent [Orphanet] 21438134 IBIS 192 / 7739
28
(HPO:0001639) Hypertrophic cardiomyopathy Frequent [IBIS] 47% (n=40) 16329078 IBIS 137 / 7739
29
(HPO:0002119) Ventriculomegaly 26246091 IBIS 253 / 7739
30
(HPO:0001642) Pulmonic stenosis 21438134 IBIS 89 / 7739
31
(HPO:0011675) Arrhythmia Frequent [IBIS] 42% (n=40) 16329078 IBIS 226 / 7739
32
(HPO:0005110) Atrial fibrillation 21438134 IBIS 71 / 7739
33
(HPO:0011701) Multifocal atrial tachycardia 23429430 IBIS 7 / 7739
34
(HPO:0001699) Sudden death 22926243 IBIS 34 / 7739
35
(HPO:0000824) Growth hormone deficiency Frequent [IBIS] 45% (n=33) 16329078 IBIS 56 / 7739
36
(HPO:0000158) Macroglossia Frequent [Orphanet] 12641690 IBIS 119 / 7739
37
(HPO:0001252) Muscular hypotonia Frequent [IBIS] 72% (n=33) 16329078 IBIS 990 / 7739
38
(HPO:0009588) Vestibular Schwannoma 11857556 IBIS 3 / 7739
39
(HPO:0001260) Dysarthria 15940703 IBIS 329 / 7739
40
(HPO:0001263) Global developmental delay 21438134 IBIS 853 / 7739
41
(HPO:0001249) Intellectual disability Frequent [IBIS] 21495179 IBIS 1089 / 7739
42
(HPO:0001270) Motor delay 21438134 IBIS 322 / 7739
43
(HPO:0002870) Obstructive sleep apnea 21438134 IBIS 16 / 7739
44
(HPO:0100543) Cognitive impairment 21438134 IBIS 230 / 7739
45
(HPO:0000750) Delayed speech and language development 21495179 IBIS 197 / 7739
46
(HPO:0002015) Dysphagia Occasional [Orphanet] 15940703 IBIS 301 / 7739
47
(HPO:0001250) Seizures 21438134 IBIS 1245 / 7739
48
(HPO:0001561) Polyhydramnios Frequent [IBIS] Frequent [Orphanet] 87% (n=33) 16329078 IBIS 191 / 7739
49
(HPO:0009465) Ulnar deviation of finger Frequent [IBIS] Frequent [Orphanet] 75% (n=33) 16329078 IBIS 48 / 7739
50
(HPO:0001187) Hyperextensibility of the finger joints 14521568 IBIS 12 / 7739
51
(HPO:0001762) Talipes equinovarus 8186422 IBIS 309 / 7739
52
(HPO:0006429) Broad femoral neck 21438134 IBIS 18 / 7739
53
(HPO:0001771) Achilles tendon contracture 21438134 IBIS 27 / 7739
54
(HPO:0001869) Deep plantar creases Very frequent [IBIS] 15940703 IBIS 14 / 7739
55
(HPO:0001761) Pes cavus 15940703 IBIS 225 / 7739
56
(HPO:0001838) Rocker bottom foot 15940703 IBIS 85 / 7739
57
(HPO:0001385) Hip dysplasia 21438134 IBIS 242 / 7739
58
(HPO:0006191) Deep palmar crease Very frequent [IBIS] 15940703 IBIS 16 / 7739
59
(HPO:0000256) Macrocephaly Very frequent [Orphanet] 21438134 IBIS 298 / 7739
60
(HPO:0000260) Wide anterior fontanel 19288554 IBIS 55 / 7739
61
(HPO:0000768) Pectus carinatum 21438134 IBIS 136 / 7739
62
(HPO:0000767) Pectus excavatum 21438134 IBIS 244 / 7739
63
(HPO:0000470) Short neck Very frequent [Orphanet] 19288554 IBIS 345 / 7739
64
(HPO:0002751) Kyphoscoliosis 15940703 IBIS 131 / 7739
65
(HPO:0002650) Scoliosis Frequent [IBIS] 15940703 IBIS 705 / 7739
66
(HPO:0000938) Osteopenia 15940703 IBIS 138 / 7739
67
(HPO:0000939) Osteoporosis 23429430 IBIS 129 / 7739
68
(HPO:0001382) Joint hypermobility Frequent [IBIS] Frequent [Orphanet] 14521568 IBIS 231 / 7739
69
(HPO:0001388) Joint laxity 21438134 IBIS 117 / 7739
70
(HPO:0100550) Tendon rupture Frequent [Orphanet] 11146354 IBIS 17 / 7739
71
(HPO:0002750) Delayed skeletal maturation Very frequent [Orphanet] 24246682 IBIS 250 / 7739
72
(HPO:0001595) Abnormality of the hair Frequent [IBIS] Occasional [Orphanet] 23429430 IBIS 89 / 7739
73
(HPO:0008070) Sparse hair 21438134 IBIS 94 / 7739
74
(HPO:0002212) Curly hair 23429430 IBIS 21 / 7739
75
(HPO:0001808) Fragile nails 8213898 IBIS 21 / 7739
76
(HPO:0000527) Long eyelashes 21438134 IBIS 46 / 7739
77
(HPO:0001231) Abnormality of the fingernails Very frequent [Orphanet] 8213898 IBIS 116 / 7739
78
(HPO:0001800) Hypoplastic toenails Frequent [Orphanet] 8213898 IBIS 74 / 7739
79
(HPO:0001816) Thin nail 8213898 IBIS 11 / 7739
80
(HPO:0002020) Gastroesophageal reflux Frequent [IBIS] 15940703 IBIS 101 / 7739
81
(HPO:0002021) Pyloric stenosis 18247425 IBIS 51 / 7739
82
(HPO:0002240) Hepatomegaly 19288554 IBIS 467 / 7739
83
(HPO:0000823) Delayed puberty 21438134 IBIS 65 / 7739
84
(HPO:0000028) Cryptorchidism 21438134 IBIS 347 / 7739
85
(HPO:0000035) Abnormality of the testis Frequent [Orphanet] 21438134 IBIS 296 / 7739
86
(HPO:0001999) Abnormal facial shape Very frequent [IBIS] 23429430 IBIS 169 / 7739
87
(HPO:0000280) Coarse facial features Occasional [Orphanet] 21438134 IBIS 189 / 7739
88
(HPO:0100729) Large face Occasional [Orphanet] 21438134 IBIS 19 / 7739
89
(HPO:0000331) Short chin 19288554 IBIS 33 / 7739
90
(HPO:0002003) Large forehead 21438134 IBIS 9 / 7739
91
(HPO:0000218) High palate 24668879 IBIS 356 / 7739
92
(HPO:0002705) High, narrow palate Very frequent [Orphanet] 24668879 IBIS 308 / 7739
93
(HPO:0000164) Abnormality of the teeth Frequent [Orphanet] 24668879 IBIS 291 / 7739
94
(HPO:0000682) Abnormality of dental enamel Very frequent [Orphanet] 21438134 IBIS 102 / 7739
95
(HPO:0000289) Broad philtrum 21438134 IBIS 11 / 7739
96
(HPO:0000343) Long philtrum 21438134 IBIS 262 / 7739
97
(HPO:0000215) Thick upper lip vermilion 21438134 IBIS 17 / 7739
98
(HPO:0000154) Wide mouth 21438134 IBIS 137 / 7739
99
(HPO:0000463) Anteverted nares 22495892 IBIS 305 / 7739
100
(HPO:0005280) Depressed nasal bridge Very frequent [Orphanet] 21438134 IBIS 381 / 7739
101
(HPO:0000286) Epicanthus Frequent [Orphanet] 21438134 IBIS 371 / 7739
102
(HPO:0005989) Redundant neck skin Frequent [Orphanet] 20979192 IBIS 40 / 7739
103
(HPO:0000363) Abnormality of earlobe 21438134 IBIS 4 / 7739
104
(HPO:0009748) Large earlobe Occasional [Orphanet] 21438134 IBIS 27 / 7739
105
(HPO:0000369) Low-set ears 19288554 IBIS 372 / 7739
106
(HPO:0000358) Posteriorly rotated ears 21438134 IBIS 163 / 7739
107
(HPO:0000951) Abnormality of the skin Very frequent [Orphanet] 15940703 IBIS 147 / 7739
108
(HPO:0000956) Acanthosis nigricans Very frequent [Orphanet] 8213898 IBIS 54 / 7739
109
(HPO:0000957) Cafe-au-lait spot 21438134 IBIS 84 / 7739
110
(HPO:0000953) Hyperpigmentation of the skin Occasional [Orphanet] 8213898 IBIS 75 / 7739
111
(HPO:0003764) Nevus 22098123 IBIS 17 / 7739
112
(HPO:0000973) Cutis laxa 19288554 IBIS 43 / 7739
113
(HPO:0000962) Hyperkeratosis Very frequent [IBIS] Very frequent [Orphanet] 15940703 IBIS 216 / 7739
114
(HPO:0001028) Hemangioma 21438134 IBIS 23 / 7739
115
(HPO:0200043) Verrucae 25787333 IBIS 11 / 7739
116
(HPO:0001582) Redundant skin Very frequent [Orphanet] 19288554 IBIS 51 / 7739
117
(HPO:0000083) Renal insufficiency Rare [IBIS] rare [HPO:skoehler] 18039947 IBIS 232 / 7739
118
(HPO:0001724) Aortic dilatation 21438134 IBIS 24 / 7739
119
(HPO:0002664) Neoplasm Occasional [IBIS] 15% (n=40) 16329078 IBIS 111 / 7739
120
(HPO:0002862) Bladder carcinoma 24169525 IBIS 2 / 7739
121
(HPO:0002859) Rhabdomyosarcoma 24637993 IBIS 10 / 7739
122
(HPO:0001548) Overgrowth Frequent [IBIS] 65% (n=11) 19288554 IBIS 27 / 7739
123
(HPO:0001622) Premature birth 19288554 IBIS 100 / 7739
124
(HPO:0030680) Abnormality of cardiovascular system morphology Frequent [IBIS] 23429430 IBIS 355 / 7739
125
(HPO:0007099) Arnold-Chiari type I malformation Frequent [IBIS] 21495179 IBIS 18 / 7739
126
(HPO:0002059) Cerebral atrophy 14608654 IBIS 171 / 7739
127
(HPO:0030148) Heart murmur 19288554 IBIS 29 / 7739
128
(HPO:0000238) Hydrocephalus Frequent [IBIS] 23429430 IBIS 278 / 7739
129
(HPO:0040169) Loose anagen hair 21438134 IBIS 2 / 7739
130
(HPO:0012758) Neurodevelopmental delay Frequent [Orphanet] 21495179 IBIS 949 / 7739
131
(HPO:0012740) Papilloma Frequent [IBIS] Frequent [Orphanet] 47% (n=40) 16329078 IBIS 17 / 7739
132
(HPO:0003396) Syringomyelia 23429430 IBIS 16 / 7739
133
(OMIM) Posterior fossa crowding, progressive 21438134 IBIS 1 / 7739

Associated genes:

HRAS;

ClinVar (via SNiPA)

Gene symbol Variation Clinical significance Reference
HRAS rs104894226 pathogenic RCV000013438.24
HRAS rs104894227 pathogenic RCV000013439.24
HRAS rs104894228 pathogenic RCV000013440.26
HRAS rs104894229 pathogenic RCV000013447.26
HRAS rs104894229 pathogenic RCV000013435.28
HRAS rs104894230 pathogenic RCV000038460.2
HRAS rs104894230 pathogenic RCV000013437.24
HRAS rs104894230 pathogenic RCV000013432.26
HRAS rs104894231 pathogenic RCV000013441.17
HRAS rs121917757 likely pathogenic RCV000143898.1
HRAS rs121917758 pathogenic RCV000013444.18
HRAS rs398122808 pathogenic RCV000022797.22
HRAS rs398122809 pathogenic RCV000022798.24
HRAS rs587777239 pathogenic RCV000106320.2
HRAS rs727503093 likely pathogenic RCV000150835.1
HRAS rs727503094 likely pathogenic RCV000150836.1
HRAS rs727504747 likely pathogenic RCV000156047.1

Additional Information:

Description: (OMIM) Costello syndrome is a rare multiple congenital anomaly syndrome associated in all cases with a characteristic coarse facies, short stature, distinctive hand posture and appearance, severe feeding difficulty, and failure to thrive. Other features include cardiac anomalies and ...
Diagnosis OMIM Smith et al. (2009) reviewed prenatal ultrasound findings of 17 patients with Costello syndrome. Seven (41%) were preterm with delivery prior to 37 weeks' gestation, and the remaining 10 (59%) were term deliveries. There were 3 main prenatal ...
Clinical Description OMIM Costello (1977) described 2 unrelated children with a syndrome comprising short stature, redundant skin of the neck, palms, soles, and fingers, curly hair, papillomata around the mouth and nares, and mental retardation. Der Kaloustian et al. (1991) reported ...
Genotype-Phenotype Correlations OMIM Gripp et al. (2007) reported 13 unrelated patients ages 0 to 8 years with a clinical diagnosis of Costello syndrome, Costello-like syndrome, or thought to have either CFC syndrome or Costello syndrome who were negative for mutations in ...
Molecular genetics OMIM Because of phenotypic overlap between Costello syndrome and Noonan syndrome (163950), and because mutations in the SHP2/PTPN11 gene (176876) had been demonstrated in the latter, Tartaglia et al. (2003) screened a cohort of 27 patients with clinically diagnosed ...
Diagnosis GeneReviews Costello syndrome is diagnosed clinically. Formal diagnostic criteria for Costello syndrome have not been developed, but have been published as informal consensus guidelines developed by experts [Kerr et al 2010 (see Table 16.1), Gripp & Lin 2011]. No single feature is unique for Costello syndrome, although the constellation of several features creates the characteristic phenotype. Clinicians should view these guidelines in the context of the natural history....
Clinical Description GeneReviews Females and males are equally affected. Costello syndrome can theoretically be recognized in the fetus, is usually diagnosed in the young child, and evolves with age, with older individuals displaying features of premature aging....
Genotype-Phenotype Correlations GeneReviews Because few affected individuals with mutations other than p.Gly12Ser have been identified, limited genotype-phenotype correlations have been established. However, Kerr et al [2006] suggested that the risk for malignant tumors may be higher in individuals with the p.Gly12Ala mutation (4/7; 57%) than in those with the p.Gly12Ser variant (4/65; 7%). No individuals with p.Gly13Cys have developed a malignant tumor to date [Gripp et al 2011a]....
Differential Diagnosis GeneReviews In infants and young children, Costello syndrome is difficult to distinguish from cardiofaciocutaneous (CFC) syndrome or Noonan syndrome; in older children, the distinction between Costello syndrome and Noonan syndrome is clear. Feeding problems and failure to thrive are usually more severe in infants with Costello syndrome and CFC syndrome than in infants with Noonan syndrome. The distinctive combination of pectus carinatum and pectus excavatum typifies Noonan syndrome. Costello syndrome is distinguished by ulnar deviation of the hands, marked small-joint laxity, striking excess palmar skin, the presence of papillomata, and palmar calluses....
Management GeneReviews To establish the extent of disease in an individual diagnosed with Costello syndrome, the following evaluations are recommended:...
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....