Page 29 - Clinical variability in Noonan syndrome with emphasison ear and eye

VARIABLE PHENOTYPIC EXPRESSION IN A LARGE NOONAN SYNDROME FAMILY
Introduction
Noonan syndrome (NS) is an autosomal dominant condition characterized by facial features, congenital heart defects, short stature, ocular manifestations, skeletal abnormalities, lymphoedema and learning problems (1,2). The first NS gene, PTPN11, has been elucidated in 2001. Gain-of-function mutations in PTPN11 are responsible for approximately 50% of all cases with NS (3). Since 2001, other NS-genes have been identified. Germline mutations in these genes, leading to dysregulation of the RAS- MAPK pathway, give NS and NS-like conditions. The genes now known are: SOS1, BRAF, RAF1, SHOC2, KRAS, NRAS, MAP2K1, MAP2K2, RIT1, CBL, SOS2, PPP1CB, MRAS and LZTR1 (4-13). The second most common gene involved in NS is SOS1, described in 10-20% of NS cases (14). The Son of Sevenless homolog 1 (SOS1) gene encodes a guanine nucleotide exchange factor (GEF) for RAS proteins. The product of this gene may regulate RAS proteins by facilitating the change between inactive (GDP-bound) and active (GTP-bound) states (15). Frequent clinical manifestations in NS patients with SOS1 mutations are ectodermal abnormalities (including sparse eyebrows, dry skin, keratosis pilaris), cardiac abnormalities and facial features (16). Cognitive impairment and reduced growth due to SOS1 mutations are described less frequently compared to the total NS population (17).
Different studies report on genotype-phenotype correlations for patients with NS due to a SOS1 mutation (18,19). Noonan syndrome due to pathogenic SOS1 mutations is described as a recognizable distinctive form of Noonan syndrome with ectodermal abnormalities but normal growth and development (20). On the other hand the difficulty of predicting a genotype based on characteristic clinical features in NS is frequently reported (21). One small NS family is described with different clinical characteristics between three family members with the same familial SOS1 mutation (22). Furthermore, the photographs of 5 generations in a SOS1 family are shown but no further information about the mutation and the characteristics is presented (23).
In this observational study we describe in detail the variable clinical features of ten genetically affected family members due to a new SOS1 mutation. To the best of our knowledge, this is the first report of a large NS family due to a SOS1 mutation describing the phenotype extensively.
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