Noonan syndrome is a relatively common, autosomal-dominant, inherited disorder.
Characteristic phenotype includes short stature, chest deformity, congenital heart defects, and unusual facial features.
Boys frequently present with cryptorchidism and manifest delayed puberty.
Caused by activating mutations in multiple genes in the Ras/mitogen-activated protein kinase (MAPK) signal transduction pathway. The most commonly implicated gene is PTPN11.
Treatment focuses on the individual symptom, and may include surgery for undescended testes in boys, optimization of cardiac function, and growth hormone treatment for short stature.
The majority of patients lead normal lives. Prognosis is largely dependent on the type and severity of cardiac disease, which may occur in 50% to 80% of cases.
Noonan syndrome (NS) is a relatively common, autosomal-dominant, inherited disorder that is predominantly characterized by short stature, subtle facial dysmorphisms, chest deformity, congenital heart disease, and variable degrees of developmental delay. Coagulation defects, cryptorchidism in men, and lymphatic dysplasia are not uncommon.
The syndrome is thought to be caused primarily by gain-of-function (activating) mutations in genes in the Ras/mitogen-activated protein kinase (MAPK) signal transduction pathway. Genes implicated include: PTPN11, SOS1, RAF1, RIT1, RASA2, LZTR1, SOS2, CBL, KRAS, NRAS, BRAF, PPP1CB, and MAP2K1. The most commonly identified genetic mutation involves PTPN11.
Noonan syndrome caused by SHOC2 mutation is now considered by most to be an overlapping condition with unusual features (loose anagen hair); some consider it to be a distinct condition, while others consider it to be classified only as Noonan syndrome.
History and exam
Key diagnostic factors
- positive family history
- short stature
- dysmorphic facial features
- cardiac anomalies
- delayed puberty
- easy bruising or bleeding
- pigmentary anomalies
- sparse or absent eyebrows and lashes
Other diagnostic factors
- abnormalities identified prenatally
- chest deformity
- developmental delay/learning difficulty
- skeletal anomalies
- muscle weakness
- history of renal malformation
- family history of NS
- advanced paternal age
1st investigations to order
Investigations to consider
- coagulation profile
- molecular genetic testing
- abdominal ultrasound
- renal ultrasound
David A. Stevenson, MD
Department of Pediatrics
Division of Medical Genetics
DAS has acted as a consultant for Lineagen, GLG, and Alexion, and has given expert testimony. He is on the medical advisory board for parents' support groups for Costello syndrome and CFC syndrome. DAS is an author of a reference cited in this topic. DAS has also been reimbursed by RASopathies Network for attending conferences.
Dr David A. Stevenson would like to gratefully acknowledge Dr Judith E. Allanson, the previous contributor to this topic. JEA is an author of a number of references cited in this topic.
Liliana N. Contreras, MD
Endocrine Research Department
Instituto de Investigaciones Médicas Alfredo Lanari
University of Buenos Aires
LNC declares that she has no competing interests.
Bruce Gelb, MD
Professor of Pediatrics
Mount Sinai School of Medicine
BG received royalties from GeneDx, Correlegan, Preventative Genetics, Baylor College of Medicine, and Harvard Medical School/Partners for genetic testing of Noonan syndrome. BG is an author of a number of references cited in this topic.
Jacqueline Noonan, MD
Department of Pediatrics
College of Medicine
University of Kentucky
JN is on the Noonan Syndrome Advisory Board for Novo Nordisk and has received payment for speaking at a symposium. JN is an author of a number of references cited in this topic.
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