Noonan syndrome is a pleiomorphic autosomal dominant disorder with cardinal features such as short stature, distinctive facial dysmorphia, webbed neck, and heart defects. The condition was described more than half a century ago, and in the past decade significant progress has been made in elucidating the pathogenesis and genetics of this disorder.

Discovery of the syndrome

The first reported patient with what is now called Noonan syndrome was reported by Kobylinski in 1883. The individual in question was a 20-year old male with marked webbing of the neck, which was a feature that seemed to prompt a majority of the early reports.

In 1902, Funke described a patient with a webbed neck, who also presented with a short stature, cubitus valgus (a deformity of the elbow), micrognathia (undersized jaw) and other minor abnormalities. This publication was followed by a report by Ullrich in 1930 who described 8-year old girl with similar features.

Chromosomal basis for the Turner syndrome was initially reported in 1959. Reports of so-called “male Turner syndrome” or Turner phenotype have been abundant throughout the 1960s, but a vigorous attempt to find an underlying chromosomal abnormality was unsuccessful. Later it has been demonstrated that most of these reports describe a different clinical entity.

In 1962, a pediatric cardiologist Jacqueline Noonan presented a clinical study of associated non-cardiac malformations in children with congenital heart disease at the Midwest Society for Pediatric Research, where she also described nine patients that shared distinctive facial features and who had a short stature, pulmonary stenosis and significant chest deformities.

In 1968 she published these nine and an additional ten patients in the American Journal of Diseases of Children. Pediatrician John Opitz proposed the eponym Noonan syndrome, which was adopted in recognition of dr. Noonan, as she was the first to indicate that this condition occurs in both sexes, is familial in certain cases, includes congenital heart defects and is associated with normal chromosomes.

History of genetic research

In 1994, the gene for Noonan syndrome was mapped to the long arm of chromosome 12 and named NS1. Still, one family did not link, which suggested that more than one gene was involved in the condition. In 2001, Tartaglia and his co-workers found a mutation in the protein tyrosine phosphatase non–receptor type 11 gene (PTPN11), which was the first molecular cause of Noonan syndrome.

Observations that PTPN11 occupied the critical region of NS1 enabled this discovery. Subsequent studies of PTPN11 deficiency in a mouse model revealed that its protein product, tyrosine phosphatase SHP-2, was pivotal for the embryologic development of the semilunar cardiac valves.

It has been also confirmed that mutations in the PTPN11 gene have a very high incidence of congenital heart disease of at least 80%. Pulmonary valve stenosis was a most common finding, which is the reason why investigators thought that PTPN11 was a leading positional candidate gene in NS1.

In the recent years additional genes have been identified (such as KRAS, RAF1 and SOS1) that have a role in the pathogenesis of this condition. Subsequent molecular discovery indicated that other genetic syndromes with phenotypic resemblance to Noonan syndrome – namely Costello and cardiofaciocutaneous syndromes – proved not to be allelic.

Noonan syndrome is now known to be a genetically heterogeneous disorder with practically one half of all cases caused by gain-of-function mutations in PTPN11, the gene encoding the SHP-2. The currently available commercial tests are constructed to detect the existence of missense or small insertions/deletions in the coding regions and flanking intron boundaries of genes that cause Noonan syndrome.