Submitted Successfully!
To reward your contribution, here is a gift for you: A free trial for our video production service.
Thank you for your contribution! You can also upload a video entry or images related to this topic.
Version Summary Created by Modification Content Size Created at Operation
1
Giovanna Scorrano
 -- 2316 2023-12-06 09:50:37 |
2 format correct
Catherine Yang
 Meta information modification 2316 2023-12-06 09:56:25 |

Video Upload Options

Do you have a full video?
Send video materials Upload full video

Confirm

Are you sure to Delete?
Yes No
Cite
If you have any further questions, please contact Encyclopedia Editorial Office.
Scorrano, G.; David, E.; Calì, E.; Chimenz, R.; La Bella, S.; Di Ludovico, A.; Di Rosa, G.; Gitto, E.; Mankad, K.; Nardello, R.; et al. The Cardiofaciocutaneous Syndrome. Encyclopedia. Available online: https://encyclopedia.pub/entry/52420 (accessed on 17 May 2024).
Scorrano G, David E, Calì E, Chimenz R, La Bella S, Di Ludovico A, et al. The Cardiofaciocutaneous Syndrome. Encyclopedia. Available at: https://encyclopedia.pub/entry/52420. Accessed May 17, 2024.
Scorrano, Giovanna, Emanuele David, Elisa Calì, Roberto Chimenz, Saverio La Bella, Armando Di Ludovico, Gabriella Di Rosa, Eloisa Gitto, Kshitij Mankad, Rosaria Nardello, et al. "The Cardiofaciocutaneous Syndrome" Encyclopedia, https://encyclopedia.pub/entry/52420 (accessed May 17, 2024).
Scorrano, G., David, E., Calì, E., Chimenz, R., La Bella, S., Di Ludovico, A., Di Rosa, G., Gitto, E., Mankad, K., Nardello, R., Mangano, G.D., Leoni, C., & Ceravolo, G. (2023, December 06). The Cardiofaciocutaneous Syndrome. In Encyclopedia. https://encyclopedia.pub/entry/52420
Scorrano, Giovanna, et al. "The Cardiofaciocutaneous Syndrome." Encyclopedia. Web. 06 December, 2023.
The Cardiofaciocutaneous Syndrome
Edit
This entry is adapted from the peer-reviewed paper 10.3390/genes14122111

Cardiofaciocutaneous (CFC) syndrome is one of the rarest RASopathies characterized by multiple congenital ectodermal, cardiac and craniofacial abnormalities with a mild to severe ocular, gastrointestinal and neurological involvement. It is an autosomal dominant syndrome, with complete penetrance, caused by heterozygous pathogenic variants in the genes BRAF, MAP2K1/MEK1, MAP2K2/MEK2, KRAS or, rarely, YWHAZ, all part of the RAS-MAPK pathway. This pathway is a signal transduction cascade that plays a crucial role in normal cellular processes such as cell growth, proliferation, differentiation, survival, metabolism and migration. CFC syndrome overlaps with Noonan syndrome, Costello syndrome, neurofibromatosis type 1 and Legius syndrome, therefore making the diagnosis challenging.

Cardiofaciocutaneous syndrome CFC neurodevelopment hypertrophic cardiomyopathy

1. Introduction

CFC syndrome (OMIM 115150) is a multisystemic disorder that affects 1 in 800,000 newborns. CFC belongs to a group of syndromes collectively known as “RASopathies”, caused by germline mutations in one of the genes encoding components of the RAS-MAPK signal transduction pathway [1][2]. The RAS-MAPK pathway is a signal transduction cascade that plays a crucial role in normal cellular processes such as cell growth, proliferation, differentiation, survival, metabolism and migration. Somatic gain-of-function mutations in RAS genes are a well-known cause of cancer and there has been an increasing number of studies involving the RAS pathway in oncogenesis [3]. Though each syndrome has its specific phenotype, many of the RASopathies have overlapping clinical features, therefore making the diagnosis challenging. These can include facial dysmorphisms, intellectual disability (ID), congenital heart disease, short stature, muscle skeletal anomalies and lymphatic dysfunction. CFC syndrome may clinically overlap with neurofibromatosis type 1 (NF1), Noonan syndrome (NS), Noonan syndrome with multiple lentigines (NS-ML), Costello syndrome (CS), Legius syndrome (LS), central conducting lymphatic anomalies syndrome (CCLA), SYNGAP1 syndrome, and capillary malformation arteriovenous malformation syndrome (CM-AVM), though compared with other RASopathies, it exhibits more severe neurologic complications and phenotype [4]. CFC patients frequently present with a characteristic facial appearance, congenital heart disease, severe developmental delay and psychomotor delay, ectodermal, ocular and gastrointestinal abnormalities, and neurological involvement [1]. Characteristic facial features include high forehead, bitemporal constriction, supraorbital hypoplasia, downslanting palpebral fissures, depressed nasal bridge and posteriorly rotated ears with thick helices [5][6]. Compared to other RASopathies, neurological involvement is more severe and commonly includes refractory epilepsy, neurocognitive impairment, motor and speech deficits, hypotonia and behavioral challenges; ventriculomegaly, cortical atrophy and hydrocephalus are the most frequent imaging findings in CFC patients [6][7]. Cardiac involvement is common in CFC and manifests as atrial and ventricular septal defects, hypertrophic cardiomyopathy and pulmonary valve stenosis. These patients also have curly and friable hair, and sparse eyebrows and eyelashes; skin involvement ranges from dry skin to hyperkeratosis. CFC is inherited in an autosomal-dominant manner, and most pathogenic variants involve the genes BRAF (75%), MAP2K1 (25%), MAP2K2 (25%), KRAS (2%) or, more rarely, YWHAZ [8]. The real incidence is still unknown and a phenotypic variability related to the specific gene affected has been identified, without a genotype–phenotype correlation for specific pathogenic variants (Table 1) [5]. The diagnosis of CFC syndrome is suspected based on the distinctive clinical features and it is confirmed by molecular genetic testing [5][9]. The aim of the study is to give updated evidence on the pathogenesis, clinical and radiological features, diagnosis, and available treatment for CFC, supplying practice guidelines for the management of pediatric patients with CFC.
Table 1. Genetic findings in patients with CFC.
Gene OMIM Number Prevalence Inheritance CFC Phenotypic Features
BRAF *164757 75%
  • De novo missense heterozygous variants
  • Autosomal-dominant missense variant inherited by mother (1 case)
 Moderate to severe polymorphic seizures (+exons 11–16) 57%
Moderate ID 89%
Motor delay and hypotonia (unable to walk, needing support) 29%
Cardiac disease 72%
Greater risk of skin abnormalities
Ocular hypertelorism, optic nerve hypoplasia
Tumors (+melanoma, thyroid, colorectal, and ovarian cancers, benign nevi, premalignant colon polyps 8%
Pulmonary stenosis 50%
MAP2K1 *176872 25% De novo missense heterozygous variants Moderate to severe polymorphic seizures (+p.Y130C/H/N variant, exon 3) 61%
Mild ID 84%
Motor delay and hypotonia (unable to walk, needing support) 71%
Cardiac disease (lower frequency, NA)
Macrocephaly, high forehead, bitemporal constriction, hypoplasia of the supraorbital ridges, downslanting palpebral fissures
Musculoskeletal abnormalities
MAP2K2 *601263 25%
  • De novo missense heterozygous variants
  • Autosomal dominant missense variants inherited by mother (4 cases)
 Lower risk of seizure occurrence and less severe seizure types 30%
Mild ID 25%
Motor delay and hypotonia (unable to walk, needing support) 13%
Cardiac disease 64%
Macrocephaly, high forehead, bitemporal constriction, hypoplasia of the supraorbital ridges, downslanting palpebral fissures
KRAS *190070 2%
  • De novo missense heterozygous variants
  • Autosomal dominant missense variants inherited by mother (2 cases)
 No epilepsy
Neurodevelopmental delay
Coarse face
Cardiac defects
YWHAZ *601288 Rarely, NA De novo missense heterozygous variants Developmental delay, behavioural disorders
ID
Short stature
Motor and speech delay
Triangular facies, ptosis
Seizures
Feeding problems

2. Neurological Findings

Neurological involvement in CFC syndrome is present in nearly all individuals and ranges from mild to severe. Developmental delay, ID, epilepsy and hypotonia are common findings, although a few individuals may have normal cognitive function (IQ within normal range).
In children with CFC, seizures frequently occurred, usually with onset in infancy or early childhood and they included tonic–clonic and/or complex focal seizures, absence seizures and epileptic infantile spasms [7][10][11][12][13][14]; seizures could occur later in infancy, requiring polytherapy and refractoriness to antiseizure medications (ASMs) [5]. However, in children, seizure may occur also due to multiple different genetic conditions [15][16][17][18].
Hypotonia is also described and presented typically with a neonatal onset with mild to severe asthenia, motor delay and poor muscle mass [5]. Furthermore, behavior abnormalities could characterize a neuropsychiatric disorder in CFC patients, including irritability, obsessive compulsive disorder, anxiety and autistic traits [5][19].
A recent clinical study by Pierpont et al. [6] reported a higher rate of CFC patients affected by epilepsy than in the previously published literature: seizures of various type occurred in 57% of individuals with BRAF pathogenic variants, 61% of patients with MAP2K1 pathogenic variants and 30% of subjects with MAP2K2 pathogenic variants. MAP2K2 mutations were associated with a lower risk of seizure occurrence and less severe seizure types [6]. On the other hand, patients with pathogenic variants in BRAF and MAP2K1 presented with moderate to severe polymorphic seizures, which were frequently drug-resistant. Furthermore, a relevant study by Battaglia et al. [14] shed a light on genotype–phenotype correlation concerning the epileptic phenotype. There seems to be a strong genotype–phenotype correlation regarding the occurrence and severity of seizures, since variants in the protein kinase domain of BRAF (exons 11–16) and the p.Y130C/H/N variant of MAP2K1 (exon 3) correlate with a severe epileptic phenotype [6]. Nevertheless, pathogenic variants in KRAS variants were not associated with epilepsy. Notably, most children affected with the above genotypes and severe epilepsy were also presenting neurodevelopmental impairment. ID was reported in most individuals (82 -100%), usually carrying BRAF (89%) or MAP2K1 (84%) pathogenic variants, while it was described only in 25% of patients with MAP2K2 pathogenic variants [6]. The degree of ID ranged from mild (MEK) to moderate (BRAF) [20]. Neurodevelopmental delay may be mild and difficult to notice in patients with mild or moderate involvement, while speech and motor delays are usually obvious in severely affected children [21]. Nevertheless, those are non-specific findings, often found also in children with other kinds of neurologic impairment [17][22][23][24]. Motor delay and hypotonia are the most frequently observed neurological features in CFC syndrome [25]. Pierpont et al., reported a distinctive genotype–phenotype correlation: children carrying pathogenic variants in MAP2K1 showed more need for support and lack of independent ambulation (71%) compared to patients with BRAF (29%) or MAP2K2 (13%) mutations [6]. Language acquisition is usually delayed and speech abilities range from full sentences to non-verbal communications (9–31%) [9]. Interestingly, mutations promoting dysregulation of the RAS-MAPK cascade have been associated with an increased psychopathological risk. Frequently, patients with CFC presented underdiagnosed autistic-like behaviors [19].
A magnetic resonance imaging (MRI) evaluation could be useful during the diagnostic work-up. Brain magnetic resonance imaging studies may prove useful in patients with uncertain diagnosis and for prognostic information. Ventriculomegaly (43.9%) is the most common finding and sometimes requires a ventriculo-peritoneal shunt [26][27].
Other findings comprise prominent Virchow–Robin spaces (10.6%), hydrocephalus (24.2%) and myelination abnormalities. Some patients have structural brain anomalies, including Type I Chiari malformation (4.5%), arachnoid cyst (1.5%) and subependymal grey matter heterotopia (7.5%) [10].
Other abnormalities can include abnormal EEG, dilated perivascular spaces, dilated perivascular spaces, corticospinal tract findings, agenesis of the corpus callosum (6%), frontal lobe hypoplasia (1.5%), pachygyria (7.5%) and Chiari malformation (4.5%) [5] (Figure 1).
Figure 1. Neuroradiological findings in patient with CFC. Magnetic resonance imaging (MRI) scan of the brain of a 2-year-old patient with a MAP2K1 variant in CFC Syndrome. (A) Sagittal T1: Reduced cerebral volume anteriorly with associated thinning of the corpus callosum. (B) Coronal T1: Bilateral hippocampal malrotation. (C) Axial T1: Delayed myelination within the temporal lobes. (D) Axial T2: Abnormal signal within the dentate nuclei.

2.1. Cardiac Findings

Congenital heart defects (CHDs) occur in most people with CFC syndrome (~75%) [9][28][29][30]. The cardiac defects most frequently associated with this condition include pulmonary valvular stenosis (PVS) (~45%), Hypertrophic cardiomyopathy (HCM) (~40%), atrial septal defect (18–28%), ventricular septal defect (11–22%) and other anomalies such as mitral valve dysplasia, arrhythmias, tricuspid valve dysplasia, and bicuspid aortic valve [9]. Patients with MAP2K1 variants have a lower frequency of cardiac disease than those with MAP2K2 (64%) and BRAF variants (72%) [8]. Literature data show that neurological and cardiac phenotypes do not segregate in a similar pattern, so different variants in CFC genes have different consequences across tissues [6].

2.2. Ectodermal Findings

Ectodermal anomalies are cardinal features of CFC syndrome; virtually all patients with CFC syndrome develop some kind of ectodermal involvement.
The most common manifestations are sparse, curly, fine, brittle slow-growing hair; sparse to absent eyebrows with ulerythema ophryogenes; sparse to absent eyelashes; dystrophic rapid-growing nails; skin abnormalities such as keratosis pilaris, hyperkeratosis, ichthyosis, eczemas, xerosis, hemangiomas and numerous pigmented naevi (more common in patients with BRAF mutations) [31][32][33][34]. Some skin anomalies evolve with age: xerosis and follicular hyperkeratosis can improve [35], palmoplantar hyperkeratosis tends to worsen, especially in pressure areas, lymphedema may become more severe, and pigmented naevi [36][37] tend to grow in number [38]. It is also common for CFC patients to be affected by severe skin infections [5].

2.3. Craniofacial Findings

Children with CFC syndrome have characteristic craniofacial features. Those include macrocephaly, high forehead, bitemporal constriction, hypoplasia of the supraorbital ridges, downslanting palpebral fissures (more frequent in patients with MEK mutations than BRAF), ocular hypertelorism (more commonly associated with mutations in BRAF), ptosis, epicanthal folds, telecanthus, short nose with depressed bridge and anteverted nares, low-set and posteriorly angulated ears with prominent helices, high-arched palate and relative micrognathia [9].

2.4. Gastrointestinal and Growth Findings

Feeding problems are very frequently reported, almost in all CFC patients, and there does not seem to be any genotype–phenotype correlation [39][40]. These problems are usually reported in the neonatal period and manifest as poor suck, swallow dysfunction, vomiting, gastroesophageal reflux, aspiration, and oral aversion. Feeding issues are usually followed by inadequate oral caloric intake, failure to thrive, and often require nasogastric tube feeding (40%) or gastrotomy tube placement (50%) [9]. In these children, growth is usually delayed with both weight and length below normal range [5]. Oral aversion can persist during childhood but usually GI symptoms improve with age, other than in patients with epilepsy onset in childhood. Their GI disorders become worse with age. Constipation is often seen in children with CFC, other findings include intestinal malrotation, hernia and also splenomegaly, hepatomegaly and steatosis. Many common symptoms are a consequence of dysmotility including gastroesophageal reflux, vomiting and constipation (Figure 2) [20].
Figure 2. Distinctive craniofacial features in a CFC patient through time. At 12 months (A), 5 years (B) and 16 years of age (C,D), respectively.
It is important to notice that, though the short stature could be related to a growth delay caused by poor feeding, it could also be linked to a growth hormone deficiency, since the RAS-MAPK pathway plays an important role in the insulin-like growth factor I (IGF-I) mediations and growth hormone (GH) secretion.

2.5. Additional Features

During perinatal period polyhydramnios (77%) and prematurity (up to 50%) have been reported as common findings [9][20].
The vast majority of individuals present with musculoskeletal abnormalities including hypotonia, pectus excavatum and carinatum, scoliosis, kyphosis, short neck and pterygium coli. The orthopedic features are more common in patients with MAP2K1 variant than in patients with other variants according to Leoni et al. [41]. Interestingly, patients with CFC present a reduced bone mineral density (BMD), probably associated with reduced physical activity and inflammatory cytokines. Despite vitamin D supplementation and almost normal bone metabolism biomarkers, CFC patients showed significantly decreased absolute values of DXA-assessed subtotal and lumbar BMD (p ≤ 0.05), compared to controls, with BMD z-scores and t-scores below the reference range in CFC, and normal in healthy controls [42].
Endocrine complications have been evaluated in patients with CFC. Specifically, a high prevalence of thyroid autoimmunity, with an increased risk to develop autoimmune disorders, and short stature have been described and presumably related to the dysregulation of the RAS-MAPK pathway, the reduced physical activity, the presence of inflammatory cytokines and the impaired IGF1 activity [43].
Ocular manifestations including strabismus, nystagmus, ocular hypertelorism, astigmatism, optic nerve hypoplasia, myopia, hyperopia, cortical blindness, and cataracts are present in most individuals with CFC syndrome and may result in poor visual acuity. Optic nerve hypoplasia is more commonly reported in patients with BRAF mutations [20][44].
Notably, functional limitations, pain and disability have been reported in patients with CFC. Using the Pediatric Outcomes Data Collection Instrument (PODCI) and Pediatric Evaluation of Disability Index (PEDI), an interesting study [25] documented that CFC patients presented activity limitations in the PODCI domains of upper extremity function, transfers and mobility, sport, and physical function. Concurrently, a relevant disability in the PEDI domains of daily activity, mobility, socialization and cognition was noted. Pain is highly prevalent in patients with RASopathies and CFC, as well. Specifically, musculoskeletal and abdominal pain was more frequently reported and often interfered with daily activities. Furthermore, pain negatively impacted QoL and sleeping patterns [45].
Interestingly, neoplasms, commonly observed in other RASopathies, have not been reported in CFC syndrome, even though genetic mutations causing CFC syndrome are well known to play a crucial role in development and oncogenesis. BRAF mutations have been associated with 7% of cancers [46][47], and there are few published reports of neoplasia in CFC [21][48], with only one malignancy [49][50].
Urogenital anomalies may occur in ~33% of individuals with CFC: cryptorchidism is the most common feature (66% of affected males); also, renal cysts, nephrolithiasis and bladder abnormalities may be present.

References

  1. Hebron, K.E.; Hernandez, E.R.; Yohe, M.E. The RASopathies: From pathogenetics to therapeutics. Dis. Models Mech. 2022, 15, dmm049107.
  2. Abe, Y.; Aoki, Y.; Kuriyama, S.; Kawame, H.; Okamoto, N.; Kurosawa, K.; Ohashi, H.; Mizuno, S.; Ogata, T.; Kure, S.; et al. Prevalence and clinical features of Costello syndrome and cardio-facio-cutaneous syndrome in Japan: Findings from a nationwide epidemiological survey. Am. J. Med. Genet. Part A 2012, 158, 1083–1094.
  3. Lim, J.K.M.; Leprivier, G. The impact of oncogenic RAS on redox balance and implications for cancer development. Cell Death Dis. 2019, 10, 955.
  4. Zenker, M. Clinical overview on RASopathies. Am. J. Med. Genet. C Semin. Med. Genet. 2022, 190, 414–424.
  5. Rauen, K.A. Cardiofaciocutaneous Syndrome. In GeneReviews®; Adam, M.P., Mirzaa, G.M., Pagon, R.A., Wallace, S.E., Bean, L.J., Gripp, K.W., Amemiya, A., Eds.; University of Washington: Seattle, WA, USA, 1993.
  6. Pierpont, E.I.; Kenney-Jung, D.L.; Shanley, R.; Zatkalik, A.L.; Whitmarsh, A.E.; Kroening, S.J.; Roberts, A.E.; Zenker, M. Neurologic and neurodevelopmental complications in cardiofaciocutaneous syndrome are associated with genotype: A multinational cohort study. Genet. Med. 2022, 24, 1556–1566.
  7. Kenney-Jung, D.L.; Rogers, D.J.; Kroening, S.J.; Zatkalik, A.L.; Whitmarsh, A.E.; Roberts, A.E.; Zenker, M.; Gambardella, M.L.; Contaldo, I.; Leoni, C.; et al. Infantile epileptic spasms syndrome in children with cardiofaciocutanous syndrome: Clinical presentation and associations with genotype. Am. J. Med. Genet. C Semin. Med. Genet. 2022, 190, 501–509.
  8. Popov, I.K.; Hiatt, S.M.; Whalen, S.; Keren, B.; Ruivenkamp, C.; van Haeringen, A.; Chen, M.-J.; Cooper, G.M.; Korf, B.R.; Chang, C. A YWHAZ Variant Associated With Cardiofaciocutaneous Syndrome Activates the RAF-ERK Pathway. Front. Physiol. 2019, 10, 388.
  9. Pierpont, M.E.M.; Magoulas, P.L.; Adi, S.; Kavamura, M.I.; Neri, G.; Noonan, J.; Pierpont, E.I.; Reinker, K.; Roberts, A.E.; Shankar, S.; et al. Cardio-Facio-Cutaneous Syndrome: Clinical Features, Diagnosis, and Management Guidelines. Pediatrics 2014, 134, e1149–e1162.
  10. Yoon, G.; Rosenberg, J.; Blaser, S.; Rauen, K.A. Neurological complications of cardio-facio-cutaneous syndrome. Dev. Med. Child Neurol. 2007, 49, 894–899.
  11. Aizaki, K.; Sugai, K.; Saito, Y.; Nakagawa, E.; Sasaki, M.; Aoki, Y.; Matsubara, Y. Cardio-facio-cutaneous syndrome with infantile spasms and delayed myelination. Brain Dev. 2011, 33, 166–169.
  12. Wakusawa, K.; Kobayashi, S.; Abe, Y.; Tanaka, S.; Endo, W.; Inui, T.; Iwaki, M.; Watanabe, S.; Togashi, N.; Nara, T.; et al. A girl with Cardio-facio-cutaneous syndrome complicated with status epilepticus and acute encephalopathy. Brain Dev. 2014, 36, 61–63.
  13. Adachi, M.; Abe, Y.; Aoki, Y.; Matsubara, Y. Epilepsy in RAS/MAPK syndrome: Two cases of cardio-facio-cutaneous syndrome with epileptic encephalopathy and a literature review. Seizure 2012, 21, 55–60.
  14. Battaglia, D.I.; Gambardella, M.L.; Veltri, S.; Contaldo, I.; Chillemi, G.; Veredice, C.; Quintiliani, M.; Leoni, C.; Onesimo, R.; Verdolotti, T.; et al. Epilepsy and BRAF Mutations: Phenotypes, Natural History and Genotype-Phenotype Correlations. Genes 2021, 12, 1316.
  15. Iacomino, M.; Baldassari, S.; Tochigi, Y.; Kośla, K.; Buffelli, F.; Torella, A.; Severino, M.; Paladini, D.; Mandarà, L.; Riva, A.; et al. Loss of Wwox Perturbs Neuronal Migration and Impairs Early Cortical Development. Front. Neurosci. 2020, 14, 644.
  16. Neuray, C.; Maroofian, R.; Scala, M.; Sultan, T.; Pai, G.S.; Mojarrad, M.; Khashab, H.E.; deHoll, L.; Yue, W.; Alsaif, H.S.; et al. Early-infantile onset epilepsy and developmental delay caused by bi-allelic GAD1 variants. Brain 2020, 143, 2388–2397.
  17. Manole, A.; Efthymiou, S.; O’Connor, E.; Mendes, M.I.; Jennings, M.; Maroofian, R.; Davagnanam, I.; Mankad, K.; Lopez, M.R.; Salpietro, V.; et al. De Novo and Bi-allelic Pathogenic Variants in NARS1 Cause Neurodevelopmental Delay Due to Toxic Gain-of-Function and Partial Loss-of-Function Effects. Am. J. Hum. Genet. 2020, 107, 311–324.
  18. Niestroj, L.-M.; Perez-Palma, E.; Howrigan, D.P.; Zhou, Y.; Cheng, F.; Saarentaus, E.; Nürnberg, P.; Stevelink, R.; Daly, M.J.; Palotie, A.; et al. Epilepsy subtype-specific copy number burden observed in a genome-wide study of 17 458 subjects. Brain 2020, 143, 2106–2118.
  19. Alfieri, P.; Piccini, G.; Caciolo, C.; Perrino, F.; Gambardella, M.L.; Mallardi, M.; Cesarini, L.; Leoni, C.; Leone, D.; Fossati, C.; et al. Behavioral profile in RASopathies. Am. J. Med. Genet. A 2014, 164, 934–942.
  20. Allanson, J.E.; Annerén, G.; Aoki, Y.; Armour, C.M.; Bondeson, M.-L.; Cave, H.; Gripp, K.W.; Kerr, B.; Nystrom, A.-M.; Sol-Church, K.; et al. Cardio-facio-cutaneous syndrome: Does genotype predict phenotype? Am. J. Med. Genet. 2011, 157, 129–135.
  21. Rauen, K.A.; Tidyman, W.E.; Estep, A.L.; Sampath, S.; Peltier, H.M.; Bale, S.J.; Lacassie, Y. Molecular and functional analysis of a novel MEK2 mutation in cardio-facio-cutaneous syndrome: Transmission through four generations. Am. J. Med. Genet. 2010, 152, 807–814.
  22. Steel, D.; Salpietro, V.; Phadke, R.; Pitt, M.; Gentile, G.; Massoud, A.; Batten, L.; Bashamboo, A.; Mcelreavey, K.; Saggar, A.; et al. Whole exome sequencing reveals a MLL de novo mutation associated with mild developmental delay and without “hairy elbows”: Expanding the phenotype of Wiedemann-Steiner syndrome. J. Genet. 2015, 94, 755–758.
  23. Efthymiou, S.; Salpietro, V.; Malintan, N.; Poncelet, M.; Kriouile, Y.; Fortuna, S.; De Zorzi, R.; Payne, K.; Henderson, L.B.; Cortese, A.; et al. Biallelic mutations in neurofascin cause neurodevelopmental impairment and peripheral demyelination. Brain 2019, 142, 2948–2964.
  24. Salpietro, V.; Efthymiou, S.; Manole, A.; Maurya, B.; Wiethoff, S.; Ashokkumar, B.; Cutrupi, M.C.; Dipasquale, V.; Manti, S.; Botia, J.A.; et al. A loss-of-function homozygous mutation in DDX59 implicates a conserved DEAD-box RNA helicase in nervous system development and function. Hum. Mutat. 2018, 39, 187–192.
  25. Johnson, B.; Goldberg-Strassler, D.; Gripp, K.; Thacker, M.; Leoni, C.; Stevenson, D. Function and disability in children with Costello syndrome and Cardiofaciocutaneous syndrome. Am. J. Med. Genet. A 2015, 167, 40–44.
  26. Papadopoulou, E.; Sifakis, S.; Sol-Church, K.; Klein-Zighelboim, E.; Stabley, D.L.; Raissaki, M.; Gripp, K.W.; Kalmanti, M. CNS imaging is a key diagnostic tool in the evaluation of patients with CFC syndrome: Two cases and literature review. Am. J. Med. Genet. A 2011, 155, 605–611.
  27. Weaver, K.N.; Gripp, K.W. Central nervous system involvement in individuals with RASopathies. Am. J. Med. Genet. C Semin. Med. Genet. 2022, 190, 494–500.
  28. Delogu, A.B.; Limongelli, G.; Versacci, P.; Adorisio, R.; Kaski, J.P.; Blandino, R.; Maiolo, S.; Monda, E.; Putotto, C.; De Rosa, G.; et al. The heart in RASopathies. Am. J. Med. Genet. C Semin. Med. Genet. 2022, 190, 440–451.
  29. Leoni, C.; Blandino, R.; Delogu, A.B.; De Rosa, G.; Onesimo, R.; Verusio, V.; Marino, M.V.; Lanza, G.A.; Rigante, D.; Tartaglia, M.; et al. Genotype-cardiac phenotype correlations in a large single-center cohort of patients affected by RASopathies: Clinical implications and literature review. Am. J. Med. Genet. A 2022, 188, 431–445.
  30. Hilal, N.; Chen, Z.; Chen, M.H.; Choudhury, S. RASopathies and cardiac manifestations. Front. Cardiovasc. Med. 2023, 10, 1176828.
  31. Dentici, M.L.; Sarkozy, A.; Pantaleoni, F.; Carta, C.; Lepri, F.; Ferese, R.; Cordeddu, V.; Martinelli, S.; Briuglia, S.; Digilio, M.C.; et al. Spectrum of MEK1 and MEK2 gene mutations in cardio-facio-cutaneous syndrome and genotype–phenotype correlations. Eur. J. Hum. Genet. 2009, 17, 733–740.
  32. Moss, C. RASopathies and the skin. Br. J. Dermatol. 2019, 180, 21.
  33. Kavamura, M.I.; Leoni, C.; Neri, G. Dermatological manifestations, management, and care in RASopathies. Am. J. Med. Genet. C Semin. Med. Genet. 2022, 190, 452–458.
  34. Bessis, D.; Morice-Picard, F.; Bourrat, E.; Abadie, C.; Aouinti, S.; Baumann, C.; Best, M.; Bursztejn, A.-C.; Capri, Y.; Chiaverini, C.; et al. Dermatological manifestations in cardiofaciocutaneous syndrome: A prospective multicentric study of 45 mutation-positive patients. Br. J. Dermatol. 2019, 180, 172–180.
  35. Roberts, A.; Allanson, J.; Jadico, S.K.; Kavamura, M.I.; Noonan, J.; Opitz, J.M.; Young, T.; Neri, G. The cardiofaciocutaneous syndrome. J. Med. Genet. 2006, 43, 833–842.
  36. Kiuru, M.; Urban, J.; Zhu, G.; Rybak, I.; Terrell, J.R.; Qi, L.; McPherson, J.D.; Marghoob, A.A.; Rauen, K.A. RAS pathway influences the number of melanocytic nevi in cardiofaciocutaneous and Costello syndromes. J. Am. Acad. Dermatol. 2020, 82, 1091–1093.
  37. Leoni, C.; Guerriero, C.; Onesimo, R.; Coco, V.; Di Ruscio, C.; Acampora, A.; Esposito, I.; Romano, A.; Tartaglia, M.; Genuardi, M.; et al. Melanocytic nevi in RASopathies: Insights on dermatological diagnostic handles. J. Eur. Acad. Dermatol. Venereol. 2021, 35, e83–e85.
  38. Siegel, D.H.; McKenzie, J.; Frieden, I.J.; Rauen, K.A. Dermatological findings in 61 mutation-positive individuals with cardiofaciocutaneous syndrome. Br. J. Dermatol. 2011, 164, 521–529.
  39. Onesimo, R.; Sforza, E.; Giorgio, V.; Viscogliosi, G.; Kuczynska, E.M.; Margiotta, G.; Perri, L.; Limongelli, D.; Proli, F.; De Rose, C.; et al. The “FEEDS (FEeding Eating Deglutition Skills)” over Time Study in Cardiofaciocutaneous Syndrome. Genes 2023, 14, 1338.
  40. Onesimo, R.; Giorgio, V.; Viscogliosi, G.; Sforza, E.; Kuczynska, E.; Margiotta, G.; Iademarco, M.; Proli, F.; Rigante, D.; Zampino, G.; et al. Management of nutritional and gastrointestinal issues in RASopathies: A narrative review. Am. J. Med. Genet. C Semin. Med. Genet. 2022, 190, 478–493.
  41. Leoni, C.; Romeo, D.M.; Pelliccioni, M.; Di Già, M.; Onesimo, R.; Giorgio, V.; Flex, E.; Tedesco, M.; Tartaglia, M.; Rigante, D.; et al. Musculo-skeletal phenotype of Costello syndrome and cardio-facio-cutaneous syndrome: Insights on the functional assessment status. Orphanet J. Rare Dis. 2021, 16, 43.
  42. Leoni, C.; Viscogliosi, G.; Onesimo, R.; Bisanti, C.; Massese, M.; Giorgio, V.; Corbo, F.; Tedesco, M.; Acampora, A.; Cipolla, C.; et al. Characterization of bone homeostasis in individuals affected by cardio-facio-cutaneous syndrome. Am. J. Med. Genet. A 2022, 188, 414–421.
  43. Siano, M.A.; Pivonello, R.; Salerno, M.; Falco, M.; Mauro, C.; De Brasi, D.; Klain, A.; Sestito, S.; De Luca, A.; Pinna, V.; et al. Endocrine system involvement in patients with RASopathies: A case series. Front. Endocrinol. 2022, 13, 1030398.
  44. Crincoli, E.; Leoni, C.; Viscogliosi, G.; Onesimo, R.; Mattei, R.; Tartaglia, M.; Catania, F.; Rizzo, S.; Zampino, G.; Salerni, A. Systematic ophthalmologic evaluation in cardio-facio-cutaneous syndrome: A genotype-endophenotype correlation. Am. J. Med. Genet. A 2023, 191, 2783–2792.
  45. Leoni, C.; Triumbari, E.K.A.; Vollono, C.; Onesimo, R.; Podagrosi, M.; Giorgio, V.; Kuczynska, E.; Veltri, S.; Tartaglia, M.; Zampino, G. Pain in individuals with RASopathies: Prevalence and clinical characterization in a sample of 80 affected patients. Am. J. Med. Genet. A 2019, 179, 940–947.
  46. Makita, Y.; Narumi, Y.; Yoshida, M.; Niihori, T.; Kure, S.; Fujieda, K.; Matsubara, Y.; Aoki, Y. Leukemia in Cardio-facio-cutaneous (CFC) syndrome: A patient with a germline mutation in BRAF proto-oncogene. J. Pediatr. Hematol. Oncol. 2007, 29, 287–290.
  47. Kratz, C.P.; Franke, L.; Peters, H.; Kohlschmidt, N.; Kazmierczak, B.; Finckh, U.; Bier, A.; Eichhorn, B.; Blank, C.; Kraus, C.; et al. Cancer spectrum and frequency among children with Noonan, Costello, and cardio-facio-cutaneous syndromes. Br. J. Cancer 2015, 112, 1392–1397.
  48. Niihori, T.; Aoki, Y.; Narumi, Y.; Neri, G.; Cavé, H.; Verloes, A.; Okamoto, N.; Hennekam, R.C.M.; Gillessen-Kaesbach, G.; Wieczorek, D.; et al. Germline KRAS and BRAF mutations in cardio-facio-cutaneous syndrome. Nat. Genet. 2006, 38, 294–296.
  49. Al-Rahawan, M.M.; Chute, D.J.; Sol-Church, K.; Gripp, K.W.; Stabley, D.L.; McDaniel, N.L.; Wilson, W.G.; Waldron, P.E. Hepatoblastoma and heart transplantation in a patient with cardio-facio-cutaneous syndrome. Am. J. Med. Genet. A 2007, 143, 1481–1488.
  50. Ney, G.; Gross, A.; Livinski, A.; Kratz, C.P.; Stewart, D.R. Cancer incidence and surveillance strategies in individuals with RASopathies. Am. J. Med. Genet. C Semin. Med. Genet. 2022, 190, 530–540.
More
© Text is available under the terms and conditions of the Creative Commons Attribution (CC BY) license; additional terms may apply. By using this site, you agree to the Terms and Conditions and Privacy Policy.
Upload a video for this entry
Information
Subjects: Pediatrics
Contributors MDPI registered users' name will be linked to their SciProfiles pages. To register with us, please refer to https://encyclopedia.pub/register :
Giovanna Scorrano
,
Emanuele David
,
Elisa Calì
,
Roberto Chimenz
,
Saverio La Bella
,
Armando Di Ludovico
,
Gabriella Di Rosa
,
Eloisa Gitto
,
Kshitij Mankad
,
Rosaria Nardello
,
Giuseppe Donato Mangano
,
Chiara Leoni
,
Giorgia Ceravolo
View Times: 135
Revisions: 2 times (View History)
Update Date: 06 Dec 2023
Table of Contents
    1000/1000
    Hot Most Recent
    Feedback