The History of Noonan Syndrome

The first recorded case of what is now called Noonan Syndrome was documented in 1883 by Kobylinski who reported a 20 year old patient with a webbed neck. Documented references to a syndrome carried through the following century and a half including Dr. John Optiz publically naming it Noonan Syndrome in 1968 and the discovery of the DNA mutations responsible in the 1990s, through 2007 and ongoing.

Here's how the whole story unfolds[1]:

1883: 1st reported case, 20 year old patient with webbed neck (Kobylinski)
1902: Report of patient with webbed neck and short stature (Funke)
1930: 8 year old girl with webbed neck and short stature (Ullrich)
1938: Older women with similar facial characteristics, webbed neck, short stature and sexual infantilism / delayed puberty (Turner)
1943: "Male Turner Syndrome" label introduced (Flavell)
1949: Report of a group, studied over 20 years, with a 4:1 women: men ratio showing traits similar to those developed in mice by bred by Bonnevie. This led to the label "Bonnevie-Ullrich Syndrome"
1959: 45,X Chromosome discovery for Turner Syndrome(TS) shows it to be gender specific. Therefore, sydrome in male patients is something different
1960s and 70s: With the discovery of the TS chromosome anomaly, a broader study of 48 cases showed some females previously diagnosed as TS were actually what was later called Noonan Syndrome(NS). Despite intense efforts by researchers, no chromosome anomaly could be found for NS.
1962: Clinical study presented associated noncardiac malformations in children with congenital heart disease including wider spaced eyes, low set posteriorly rotated ears, short stature and chest deformities (Noonan)
1968: Label of Noonan Syndrome introduced (Optiz)

1972: First documented case of hypertrophic cardiomyopathy (HCM) (Ehlers et al) and intestinal lymphangiectasis reported (Vallet et al)
1975: Additional cases of HCM reported (Hirsh et al) and pulmonary lymphangiectasis (Baltaxe et al)
1970s and 80s: Reports of lymphatic issues including lymphatic dysplasia
1983: Partial deficiency of Factor XI reported (Kitchens & Alexander) plus Factor VIII and XII as well as thromcytopenia and platelet dysfunction
1990s: Myeloproliferative disorders, including JMML, are reported as well as growth hormone studies undertaken and use reported
1992: Vision / eye issues and feeding issues are reported
1994: Gene mapped to chromosome 12
2001: Gene mutation on PTPN11 reported (Tartaglia et al)[2]
2006: KRAS (Schubbert et al)[2]
2007: SOS1 (Roberts et al, Tartaglia et al) and RAF1 (Pandit et al)[2]

Current / Ongoing: the search for more gene mutations continues as well as developing an understanding of how the mutations affect development at a molecular level. By understanding the very core, treatments can then be developed.

For a heavy duty medical reference on Noonan Syndrome and how the mutations disreglate the RAS pathway, your local library should be able to request a copy of "Noonan Syndrome and Related Disorders." edited by M. Zenker and published by Karger. The medical publication lists at over $200 on Chapters but an InterLibrary Loan should be able to locate a copy for you.


1. Noonan, J.A.: History of Noonan Syndrome and Related Disorders. Noonan Syndrome and Related Disorders. Karger, 2009, vol 17
2. Online Mendelian Inheritance in Man (OMIM), searched by gene
3. Genetics Home Reference: Noonan Syndrome

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