RASopathies

RASopathies are a clinically defined group of syndromes caused by changes in genes involved in the Ras/MAPK pathway.  These conditions include Noonan, LEOPARD, Costello and cardio-facio-cutaneous (CFC) syndromes, neurofibromatosis type 1 (NF1) and Legius syndrome.

The characteristic overlapping features of the various RASopathies include short stature, relative macrocephaly, a subtly distinct facial appearance, variable neurodevelopmental conditions (none to severe) and cardiac and cutaneous manifestations. Some are associated with an increased chance of malignancy.

Presenting features differ according to age and may vary considerably between individuals.

• Prenatal:
  • a raised nuchal translucency, cystic hygroma, pleural effusions and polyhydramnios; and
  • cardiac and/or renal anomalies, particularly pulmonary stenosis and renal pelvic dilatation.
•  Neonatal:
  • feeding difficulties and poor weight gain;
  • distinctive craniofacial appearance, including hypertelorism, down-slanted palpebral fissures, low-set posteriorly rotated ears, short neck with excess skin folds, low posterior hairline and coarseness of features (particularly observed in CFC and Costello syndromes);
  • cardiac anomalies, particularly pulmonary valve stenosis, branch pulmonary arch stenosis and hypertrophic cardiomyopathy;
  • undescended testes in boys; and
  • skin and hair changes, including cafe-au-lait macules (more common in neurofibromatosis type 1 (NF1) and Legius syndrome), lentigines (more common in LEOPARD syndrome, which stands for lentigines, ocular hypertelorism, pulmonary stenosis, abnormalities of genitalia, retardation of growth, deafness), dryness, eczema, keratosis pilaris with sparse curly hair (CFC syndrome) and papillomas (Costello syndrome).
• Childhood:
• • short stature with relative macrocephaly;
  • facial features similar to those listed in the neonatal period above, but with full upper eyelids or ptosis, flattened nasal bridge with bulbous root, and sometimes a lack of facial expression;
  • cardiac anomalies, particularly pulmonary valve stenosis, branch pulmonary arch stenosis and hypertrophic cardiomyopathy;
  • in some, developmental delay, mild learning difficulty or intellectual impairment; and
  • in some, a history of unusual bleeding or easy bruising.

Differential diagnoses include Turner syndrome (in females) and Williams syndrome.

The Ras/MAPK pathway plays an important role in cellular regulation and is therefore critical to development.

RASopathies result from dysregulation of this pathway due to constitutional (germline) gene variants, and demonstrate both genetic heterogeneity (several genes may cause the same phenotype) and clinical heterogeneity (the same gene can present with a different combination or severity of features).

The genes associated with each condition are listed below.

• Neurofibromatosis: NF1
• Legius syndrome: SPRED1
• Noonan syndrome: PTPN11, SOS1, RAF1, KRAS, NRAS, SHOC2, CBL, LZTR1
• LEOPARD syndrome: PTPN11, RAF1
• Costello syndrome: HRAS
• CFC syndrome: BRAF, MEK1/2, KRAS

Many of the gene variants identified in RASopathies (PTPN11, HRAS, KRAS, NRAS, RAF1, SOS1, SHOC2 and MEK1/2) are associated with gain of function, meaning they lead to overactivation of the signalling pathway. Some have different mechanisms of action, however; for example, variants in NF1, SPRED1 and LZTR1 can be loss-of-function, and certain PTPN11 variants result in a dominant negative effect, causing LEOPARD syndrome. In the dominant negative effect, the protein encoded by the copy of the gene with the variant interferes with the activity of the protein encoded by the unaffected copy of the gene.

Some gene changes are recurrent (such as HRAS p.G12/p.G13 in Costello syndrome) or have specific implications (Exon 13 PTPN11 is associated with severe biventricular hypertrophic cardiomyopathy). RASopathies are among a small number of genetic conditions in which the paternal age effect is noted.

For information about testing, see Clinical suspicion of Noonan syndrome.

Genomic counselling for RASopathies will vary depending on the specific condition or gene. Genomic testing of the affected individual and their parents is recommended, particularly as the phenotypic spectrum is wide and mildly affected parents may not have been suspected clinically.

The majority of the RASopathies are autosomal dominant conditions, which means that if one parent is affected the recurrence rate in a future pregnancy will be 50%. If parents are not found to have the same gene change identified in their child (presumed de novo), then the recurrence probability would be low (under 1%, with residual probability slightly above that of the background population due to the small possibility of germline mosaicism).

Rarely, Noonan syndrome is inherited in an autosomal recessive manner (LZTR1) and in this case, if both parents are found to be carriers of the condition, the recurrence probability in a future pregnancy is 25% (one in four).

RASopathies are multisystem disorders, and management of affected children should be delivered via a multidisciplinary team. This is likely to involve a community paediatrician (to monitor growth and development), a paediatric endocrinologist (if growth hormone therapy is being considered), a urologist (in the presence of cryptorchidism) and a cardiologist. If developmental delay and/or intellectual disability is noted, specialist educational support may be required.

For clinicians

• DYSCERNE Noonan Syndrome Guideline Development Group: Management of Noonan syndrome: A clinical guideline (PDF, 30 pages)
• GeneReviews: Noonan syndrome
• Genomics England: NHS Genomic Medicine Service (GMS) Signed Off Panels Resource
• National Human Genome Research Institute: Noonan syndrome
• NHS England: National Genomic Test Directory
• U.S. National Library of Medicine: ClinicalTrials.gov database

References:

• Aoki Y and Matsubara Y. ‘Ras/MAPK syndromes and childhood hemato-oncological diseases‘. International Journal of Hematology 2013: volume 97, pages 30–36. DOI: 10.1007/s12185-012-1239-y

For patients

• Child Growth Foundation
• DYSCERNE Noonan Syndrome Guideline Development Group: Management of Noonan syndrome: A clinical guideline (PDF, page 29)
• Noonan Syndrome Association