Introduction
Noonan syndrome (NS, MIM # 163950) is a common genetic disorder. It is
characterized by the presence of short stature, minor facial anomalies,
congenital heart defects, variable degrees of developmental delay and
intellectual disability, skeletal malformations, and coagulation
defects. 1,2
The incidence of NS is estimated to be between 1:1000 and 1:2500 live
births; there is no difference between sexes.
NS is caused by germline mutations in genes involved in the
Ras-mitogen-activated protein kinase (RAS-MAPK) pathway, while somatic
mutations are frequently found in various types of tumors. This pathway
is implicated in cell proliferation, differentiation, and survival.
PTPN11 (MIM * 176876) was the first gene to be associated with NS
and it is mutated in about 50% of individuals affected by Noonan
syndrome.
Other genes that can be involved are SOS1 (MIM * 182530),RAF1 (MIM * 164760), RIT1 (MIM * 609591), KRAS (MIM
* 190070), NRAS (MIM * 164790), BRAF (MIM * 64757)MAP2K1 (MIM * 176872), and LZTR1 (MIM * 600574).
Noonan syndrome has an autosomal dominant model of inheritance, with the
exception of certain mutations of LZTR1 gene. 3,
4
Congenital heart defects are a major problem in NS. The most frequent
anomaly is pulmonary valve stenosis, whereas hypertophic cardiomyopathy,
atrial or ventricular septal defects, tetralogy of Fallot, and branch
pulmonary artery stenosis are described in a minority of cases.5
Megalencephaly is defined as a head circumference 2 Standard Deviations
(SD) above the age- and sex-related mean, caused by an increased growth
of cerebral structures. This is due to disruptions of the normal brain
development, especially during neuronal proliferation and migration.
Megalencephaly can be evident at birth, or it can develop over time,
during infancy or childhood. 6,7 To date,
megalencephaly associated with NS has been reported only once in medical
literature, in an individual affected by megalencephaly-capillary
malformation (MCAP) syndrome (OMIM #602501) carrying a 22% mosaic
variant in PIK3CA (MIM * 171834) and a PTPN11 germline
variant. 8
Relative megalencephaly has been associated with variants inSHOC2 gene (MIM * 602775), causing Noonan syndrome-like disorder
with loose anagen hair-1 (MIM # 607721). 9