IllnessPrenatal Noonan syndrome spectrum, differential diagnosis

NGS +

[Sanger]

Noonan syndrome causes numerous health problems and morphologic stigmata. The most common features include unusual facies (broad forehead, drooping eyelids, telecanthus), short stature and heart defects. The disease begins prenatally, although milder cases are not diagnosed until infancy. In the prenatal period, affected fetuses may have increased nuchal translucency, hygroma colli, hydrops fetalis, congenital heart and kidney defects and larger amounts of amniotic fluid. Later, hypertrophic cardiomyopathy, variable cognitive deficits and skeletal, ectodermal and hematologic abnormalities occur as well. Noonan syndrome is usually inherited in an autosomal dominant manner, with variable expressivity, and therefore penetrance rates that are difficult to determine. Genetically related (allelic) disorders include Noonan-like disorder, LEOPARD and cardiofaciocutaneous syndromes caused by mutations in several of the roughly dozen genes that also cause Noonan syndrome. PTPN11 mutations are found in about half of patients with Noonan syndrome, in the SOS1 gene in 13%, in the LZTR1 gene in ~8% and in each of the RAF1 and RIT1 genes in ~5%. Less than 5% of Noonan cases show KRAS mutations, and other "Noonan genes" are mutated in <1%. The diagnosis can be confirmed by molecular genetics in >85% of affected individuals, but a normal DNA test result does not exclude the clinical diagnosis.

Reference: https://www.ncbi.nlm.nih.gov/books/NBK1124/

• Sympt.: Short stature, facial dysmorphism, spectrum of congenital heart defects
• Alias: Female pseudo-Turner syndrome
• Alias: Male Turner syndrome
• Atypical Noonan syndrome (RRAS)
• Cardiofaciocutaneous syndrome (BRAF)
• Cardiofaciocutaneous syndrome 2 (KRAS)
• Cardiofaciocutaneous syndrome 3 (MAP2K1)
• Cardiofaciocutaneous syndrome 4 (MAP2K2)
• Costello syndrome (HRAS)
• Genitopatellar syndrome (KAT6B)
• LEOPARD syndrome 1 (PTPN11)
• LEOPARD syndrome 2 (RAF1)
• LEOPARD syndrome 3 (BRAF)
• Neurofibromatosis-Noonan syndrome (NF1)
• Noonan syndrome 1 (PTPN11)
• Noonan syndrome 11 (MRAS)
• Noonan syndrome 12 (RRAS)
• Noonan syndrome 2 + 10 (LZTR1)
• Noonan syndrome 3 (KRAS)
• Noonan syndrome 4 (SOS1)
• Noonan syndrome 5 (RAF1)
• Noonan syndrome 6 (NRAS)
• Noonan syndrome 7 (BRAF)
• Noonan syndrome 8 (RIT1)
• Noonan syndrome 9 (SOS2)
• Noonan syndrome-like disorder with loose anagen hair 2 (PPP1CB)
• Noonan syndrome-like disorder with/-out juvenile myelomonocytic leukemia (CBL)
• Noonan syndrome-like with loose anagen hair 1 (SHOC2)
• SBBYSS syndrome (KAT6B)