Syndromes

The “Classic” RASopathy Syndromes

Scroll down to find information about and resources for the following germline mutation syndromes:

  • CFC syndrome (CFCS)
  • Costello syndrome (CS)
  • Neurofibromatosis type 1 (NF1)
  • Noonan Syndromes
    • Noonan syndrome (NS)
    • Legius syndrome (LS)
    • Noonan syndrome with Multiple Lentigenes (NSML)/LEOPARD syndrome
    • Noonan syndrome-like disorder with loose anagen hair (NSLAH)

 

CFC syndrome

CliffordConger19 CFC MEK2 crop

1:810,000 (Aoki et. al.); 1:150,000 (unpublished, UK)
Mutations: BRAF, KRAS, MAP2K1 (MEK1), MAP2K2 (MEK2)

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, woolly or brittle; eyelashes and eyebrows may be absent or sparse. Nails may be dystrophic or fast growing. Some form of neurologic and/or cognitive delay (ranging from mild to severe) is seen in all affected individuals. Neoplasia, mostly acute lymphoblastic leukemia (ALL), has been reported in some individuals. [Rauen KA,  GeneReviews for CFC syndrome, 2012]

External Website Links:

 

Costello syndrome (CS)

Anahita - 3 CS girls bw Portland OR

1:380,000
Mutation: HRAS

Costello syndrome (CS) is characterized by failure to thrive in infancy as a result of severe postnatal feeding difficulties; short stature; developmental delay or intellectual disability; coarse facial features (full lips, large mouth, full nasal tip); curly or sparse, fine hair; loose, soft skin with deep palmar and plantar creases; papillomata of the face and perianal region; diffuse hypotonia and joint laxity with ulnar deviation of the wrists and fingers; tight Achilles tendons; and cardiac involvement including: cardiac hypertrophy (usually typical hypertrophic cardiomyopathy [HCM]), congenital heart defect (usually valvar pulmonic stenosis), and arrhythmia (usually supraventricular tachycardia, especially chaotic atrial rhythm/multifocal atrial tachycardia or ectopic atrial tachycardia). Relative or absolute macrocephaly is typical, and postnatal cerebellar overgrowth can result in the development of a Chiari I malformation with associated anomalies including hydrocephalus or syringomyelia. Individuals with Costello syndrome have an approximately 15% lifetime risk for malignant tumors including rhabdomyosarcoma and neuroblastoma in young children and transitional cell carcinoma of the bladder in adolescents and young adults. [Gripp KW and Lin AE, GeneReviews, updated 2012]

External Costello syndrome family support website links:

Publications for families:

External website links about Costello syndrome:

 

Neurofibromatosis Type 1 (NF1)

NF1 son and mom

1:2,000 to 1:5,000
Mutation: NF1

Neurofibromatosis 1 (NF1) is characterized by multiple café au lait spots, axillary and inguinal freckling, multiple cutaneous neurofibromas, and iris Lisch nodules. Learning disabilities are present in at least 50% of individuals with NF1. Less common but potentially more serious manifestations include plexiform neurofibromas, optic nerve and other central nervous system gliomas, malignant peripheral nerve sheath tumors, scoliosis, tibial dysplasia, and vasculopathy. [Friedman JM, GeneReviews for Noonan syndrome, 2012]

External Website Links:

 

 

Hereditary Gingival Neurofibromatosis Type 1 Gingival fibromatosis is a rare overgrowth condition characterized by a benign, slowly progressive, nonhemorrhagic, fibrous enlargement of maxillary and mandibular keratinized gingiva [summary by Hart et al., 2002].

External Website Link:

 

girl wNS-Guidotti Noonan syndromes

Noonan syndrome (NS)
1:1,000 to 1:2,500
Mutations: CBL, BRAF, KRAS, MAP2K1 (MEK1), NRAS, PTPN11, RAF1, RIT1, SOS1, SOS2

Noonan syndrome (NS) is characterized by short stature, congenital heart defect, and developmental delay of variable degree. Other findings can include broad or webbed neck, unusual chest shape with superior pectus carinatum and inferior pectus excavatum, cryptorchidism, characteristic facies, varied coagulation defects, lymphatic dysplasias, and ocular abnormalities. Although birth length is usually normal, final adult height approaches the lower limit of normal. Congenital heart disease occurs in 50%-80% of individuals. Pulmonary valve stenosis, often with dysplasia, is the most common heart defect and is found in 20%-50% of individuals. Hypertrophic cardiomyopathy, found in 20%-30% of individuals, may be present at birth or develop in infancy or childhood. Other structural defects include atrial and ventricular septal defects, branch pulmonary artery stenosis, and tetralogy of Fallot. Up to one third of affected individuals have mild intellectual disability. [Allanson JE, GeneReviews for Noonan syndrome, 2012]

External Website Links:


Legius syndrome
Mutation: SPRED1

Noonan-like syndrome Legius syndrome (LS) is characterized by multiple café au lait macules without neurofibromas or other tumor manifestations of neurofibromatosis type 1 (NF1). Additional clinical manifestations reported commonly include intertriginous freckling, lipomas, macrocephaly, and learning disabilities / ADHD / developmental delays. Current knowledge of the natural history of Legius syndrome is based on the clinical manifestations of fewer than 200 individuals with a molecularly confirmed diagnosis; better delineation of the clinical manifestations and natural history of Legius syndrome will likely occur as more affected individuals are identified. [Stevenson D, Viskochil D, Mao R, Muram-Zborovski M, for GeneReviews for Legius syndrome, 2010]

External Website Links:


Noonan syndrome with multiple lentigines (NSML)/
LEOPARD syndromeLEOPARD Bowers1

Mutations: PTPN11, RAF1

Noonan syndrome with multiple lentigenes (NSML) is also known as LEOPARD syndrome (LS) is an acronym for the cardinal features lentigines, ECG conduction abnormalities, ocular hypertelorism, pulmonic stenosis, abnormal genitalia, retardation of growth, and sensorineural deafness. Multiple lentigines present as dispersed flat, black-brown macules, mostly on the face, neck and upper part of the trunk with sparing of the mucosa. In general, lentigines do not appear until age four to five years but then increase to the thousands by puberty. Some individuals with LS do not exhibit lentigines. Approximately 85% of affected individuals have heart defects, including hypertrophic cardiomyopathy (HCM) (typically appearing during infancy and sometimes progressive) and pulmonary valve stenosis. Postnatal growth retardation resulting in short stature occurs in fewer than 50% of affected persons. Sensorineural hearing deficits, present in approximately 20%, are poorly characterized. Intellectual disability, typically mild, is observed in approximately 30% of persons with LS. [Gelb BD, Tartaglia M, for GeneReviews for LEOPARD syndrome, 2010]

External Website Links:

 

Noonan syndrome-like disorder with loose anagen hair (NSLAH) NSLAH JMayoral1
Mutation: SHOC2

Paraphrased from the OMIM entry for NSLAH:

Features include short stature, facial features typical of NS including macrocephaly, high forehead, hypertelorism, palpebral ptosis, and low set and posteriorly rotated ears, short and webbed neck, redundant skin, hypernasal voices and pectus abnormalities. Also enlarged cerebrospinal fluid spaces, severe growth hormone deficiency, mild psychomotor delay with ADHD that improves with age, mild dilation of the pulmonary root, and a unique combination of ectodermal abnormalities (darkly pigmented skin with eczema or ichthyosis). Generally darkly pigmented and hairless skin. The hair of the head has the characteristics of loose anagen hair syndrome, which is easily pluckable, sparse, thin, slow-growing and generally silver-blond. Common cardiac anomalies include mitral valve and septal defects.

Mazzanti et al. (2003) suggested that the disorder in these children is distinct from Noonan syndrome.

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