Rasopathies are a group of genetic conditions caused by mutations in the Ras-MAP Kinase signaling pathway. This document discusses several Rasopathies including Noonan syndrome, which is one of the most common genetic syndromes associated with congenital heart disease. Noonan syndrome is characterized by short stature, congenital heart defects such as pulmonary stenosis, and distinctive facial features. Cardiac manifestations also include hypertrophic cardiomyopathy. Treatment for cardiac issues in Noonan syndrome follows guidelines for non-syndromic cases, but bleeding risks must be considered.

1. Dr. Ahmed Abdel
Ghany
Assisstant Lecturer, Faculty of
Medicine, Cairo University
Dr. Riem EL-Messiery
Lecturer, Faculty of Medicine,
Cairo University
RASopathies

2. WHAT ARE RASOPATHIES?

3.  The RASopathies are a group of genetic conditions, caused by
mutations in genes of the Ras-MAP Kinase pathway.

4. Syndromes caused by Rasopathies:
Cardio-Facio-
Cutaneous (CFC)
syndrome
Costello
syndrome
Noonan
syndrome
Neuro-
fibromatosis type
1 (NF1)
Legius syndrome

6. Cardio-Facial syndrome
 Incidence: 1:150,000
 Cardiac abnormalities (pulmonic stenosis and other valve
dysplasias, septal defects, hypertrophic cardiomyopathy).

7.  Cutaneous abnormalities (including
xerosis, hyperkeratosis, ichthyosis,
keratosis).
 Short neck
 Neoplasia, mostly acute
lymphoblastic leukemia (ALL).

8. Costello syndrome (CS)
 Incidence: 1:1.25 million
 Short stature; developmental delay
or intellectual disability
 Coarse facial features (full lips,
large mouth, full nasal tip)
 Diffuse hypotonia and joint laxity
with ulnar deviation of the wrists.

9. • Hypertrophic cardiomyopathy
[HCM], congenital heart defect
(usually pulmonic stenosis)
• 15% lifetime risk for malignant
tumors including rhabdo-
myosarcoma and neuro-blastoma

10. Noonan syndrome

11. What is Noonan Syndrome?
Noonan Syndrome (NS) is a
relatively common congenital
autosomal dominant disease that
affects both males and females
equally.

12. • It used to be referred to as the
male version of TURNER’S
SYNDROME; however, the
genetic causes of Noonan
syndrome and Turner
syndrome are distinct

14. •Approximately 50% of patients have gene mutations in
PTPN11, with SOS1 and RAF1 mutations
•The incidence of Noonan syndrome is estimated to be 1 case
per 1000 to 1 case per 2500 live birth.
•It is one of the most common genetic syndromes associated
with congenital heart disease, similar in frequency to Down
syndrome.

15. •The majority of patients with NS have an unremarkable
prenatal history, but about one-third of pregnancies are
complicated by polyhydramnios.
•Fetal ultrasound may reveal cystic hygroma or fetal edema.

16. Cardiac manifestations of noonan Syndrome:

17. • Most patients with NS have some cardiac abnormality. A
dysplastic often stenotic pulmonary valve is the most
characteristic lesion.
• Of particular interest is the HCM, both obstructive and non-
obstructive, which is present in 20-30% of such patients, but
virtually every type of cardiac defect has been described.

18. •Although the pulmonary valve in NS is frequently dysplastic
there is great variability in the degree of dysplasia and
obstruction. In many, the valve is only dysplastic and no
significant obstruction or regurgitation ever results.
•The majority of children with NS who have significant PS will
require surgical treatment.

19. • The natural history of HCM in NS is not yet well defined, it
is apparent that there is marked variability. The HCM may
become symptomatic and rapidly progressive in infancy, It
may remain stable for many years and may develop, or at least
become recognized late in childhood.

20. • Treatment for HCM in NS is similar to that in non-
syndromic HCM, however, patients undergoing a surgical
procedure, it is important to be aware that bleeding problems
may occur in patients with NS including factor 11 deficiency,
von Willebrand disease, thrombocytopenia and platelet
function defects.

21. •Valvular aortic stenosis, subaortic stenosis, coarctation of the
aorta, patent ductus arteriosus and ostium primum have all
been reported.

22. OTHER MANIFESTATIONS OF NOONAN

23. • Over 90% of patients with NS have a chest deformity, the
most characteristic being pectus carinatum.

24. • Lymphatic abnormalities occur in less than 20%. Besides
extremity edema, both intestinal” and pulmonary
lymphangiectasia” are occasionally seen and may lead to
protein-losing enteropathy and/or chylothorax.

25. • Abdominal examination may reveal hepatosplenomegaly in
about 25%, no explanation has been identified.
• Undescended testes, either one or both are present in about
half of affected males.
•Females with Noonan syndrome can experience delayed
puberty but most have normal puberty and fertility.

26. References:
• Sharland M, Burch M, McKenna WM, Patton MA. A clinical study of Noonan
syndrome.Arch. Dis. Child. 1992;67: 178-83.
• Vallet HL, Holtzapple PG, Eberlein WR er a/. Noonan syndrome with intestinal
lymphangiectasia. J. Pediarr: 1972; 80: 269-74.
• Maron BJ, Tajik AJ, Ruttenberg HD et al. Hypertrophic cardiomyopathy in infancy:
Clinical features and natural history.Circulation 1982;65:7- 17.
• Witt DR, McGillioray BC, Allanson JE et al. Bleeding diathesis in Noonan syndrome:
A common association. Am. J. Med. Genet. 1988;31: 305- 17.