Noonan syndrome (NS) is an autosomal dominant disorder characterised by short stature, craniofacial dysmorphism, congenital cardiac defects, cryptorchidism in men, coagulation defects, and neurocognitive delay. In addition, individuals with NS have an increased risk of developing cancer. NS is caused by germline mutations in genes that encode components or regulators of the Ras/MAPK pathway. Heterozygous, pathogenic variants in 9 known genes account for approximately 80% of cases. The most common gene associated with NS is PTPN11, which accounts for approximately 50% of all cases.
Category
Congenital malformation
Brite
Human diseases in ICD-11 classification [BR:br08403]
20 Developmental anomalies
Multiple developmental anomalies or syndromes
LD2F Syndromes with multiple structural anomalies, without predominant body system involvement
H01738 Noonan syndrome
Pathway-based classification of diseases [BR:br08402]
Signal transduction
nt06526 MAPK signaling
H01738 Noonan syndrome
Tartaglia M, Mehler EL, Goldberg R, Zampino G, Brunner HG, Kremer H, van der Burgt I, Crosby AH, Ion A, Jeffery S, Kalidas K, Patton MA, Kucherlapati RS, Gelb BD
Title
Mutations in PTPN11, encoding the protein tyrosine phosphatase SHP-2, cause Noonan syndrome.
Johnston JJ, van der Smagt JJ, Rosenfeld JA, Pagnamenta AT, Alswaid A, Baker EH, Blair E, Borck G, Brinkmann J, Craigen W, Dung VC, Emrick L, Everman DB, van Gassen KL, Gulsuner S, Harr MH, Jain M, Kuechler A, Leppig KA, McDonald-McGinn DM, Can NTB, Peleg A, Roeder ER, Rogers RC, Sagi-Dain L, Sapp JC, Schaffer AA, Schanze D, Stewart H, Taylor JC, Verbeek NE, Walkiewicz MA, Zackai EH, Zweier C, Zenker M, Lee B, Biesecker LG
Title
Autosomal recessive Noonan syndrome associated with biallelic LZTR1 variants.
Schubbert S, Zenker M, Rowe SL, Boll S, Klein C, Bollag G, van der Burgt I, Musante L, Kalscheuer V, Wehner LE, Nguyen H, West B, Zhang KY, Sistermans E, Rauch A, Niemeyer CM, Shannon K, Kratz CP
Yamamoto GL, Aguena M, Gos M, Hung C, Pilch J, Fahiminiya S, Abramowicz A, Cristian I, Buscarilli M, Naslavsky MS, Malaquias AC, Zatz M, Bodamer O, Majewski J, Jorge AA, Pereira AC, Kim CA, Passos-Bueno MR, Bertola DR
Title
Rare variants in SOS2 and LZTR1 are associated with Noonan syndrome.
Motta M, Pannone L, Pantaleoni F, Bocchinfuso G, Radio FC, Cecchetti S, Ciolfi A, Di Rocco M, Elting MW, Brilstra EH, Boni S, Mazzanti L, Tamburrino F, Walsh L, Payne K, Fernandez-Jaen A, Ganapathi M, Chung WK, Grange DK, Dave-Wala A, Reshmi SC, Bartholomew DW, Mouhlas D, Carpentieri G, Bruselles A, Pizzi S, Bellacchio E, Piceci-Sparascio F, Lissewski C, Brinkmann J, Waclaw RR, Waisfisz Q, van Gassen K, Wentzensen IM, Morrow MM, Alvarez S, Martinez-Garcia M, De Luca A, Memo L, Zampino G, Rossi C, Seri M, Gelb BD, Zenker M, Dallapiccola B, Stella L, Prada CE, Martinelli S, Flex E, Tartaglia M
Title
Enhanced MAPK1 Function Causes a Neurodevelopmental Disorder within the RASopathy Clinical Spectrum.
Motta M, Fasano G, Gredy S, Brinkmann J, Bonnard AA, Simsek-Kiper PO, Gulec EY, Essaddam L, Utine GE, Guarnetti Prandi I, Venditti M, Pantaleoni F, Radio FC, Ciolfi A, Petrini S, Consoli F, Vignal C, Hepbasli D, Ullrich M, de Boer E, Vissers LELM, Gritli S, Rossi C, De Luca A, Ben Becher S, Gelb BD, Dallapiccola B, Lauri A, Chillemi G, Schuh K, Cave H, Zenker M, Tartaglia M
Title
SPRED2 loss-of-function causes a recessive Noonan syndrome-like phenotype.
Cardio-facio-cutaneous (CFC) syndrome is a congenital disorder characterized by short stature, a characteristic face, cardiac defects, developmental delay and mental retardation. Affected individuals present with ectodermal abnormalities such as sparse, friable hair, hyperkeratotic skin lesions and a generalized ichthyosis-like condition. Typical facial characteristics include high forehead, down-slanting palpebral fissures, a depressed nasal bridge, and posteriorly angulated ears. CFC can be caused by mutations in BRAF, KRAS, MEK1, and MEK2, encoding components of the RAS-MAPK pathway.
Category
Congenital malformation
Brite
Human diseases in ICD-11 classification [BR:br08403]
20 Developmental anomalies
Multiple developmental anomalies or syndromes
LD2F Syndromes with multiple structural anomalies, without predominant body system involvement
H01745 Cardiofaciocutaneous syndrome
Pathway-based classification of diseases [BR:br08402]
Signal transduction
nt06526 MAPK signaling
H01745 Cardiofaciocutaneous syndrome
LEOPARD syndrome is an autosomal dominant developmental disorder belonging to a relatively prevalent class of inherited RAS-MAPK signalling diseases. Its main features are lentigines, electrocardiographic abnormalities, ocular hypertelorism, pulmonary valve stenosis, abnormal genitalia, retardation of growth and deafness. Approximately 90% of LEOPARD syndrome cases are caused by missense mutations in the PTPN11 gene which encodes the protein tyrosine phosphatase SHP2. But it may also be caused by mutations in RAF1 or BRAF.
Category
Congenital malformation
Brite
Human diseases in ICD-11 classification [BR:br08403]
20 Developmental anomalies
Multiple developmental anomalies or syndromes
LD2F Syndromes with multiple structural anomalies, without predominant body system involvement
H01984 Leopard syndrome
Pathway-based classification of diseases [BR:br08402]
Signal transduction
nt06526 MAPK signaling
H01984 Leopard syndrome
Carvajal-Vergara X, Sevilla A, D'Souza SL, Ang YS, Schaniel C, Lee DF, Yang L, Kaplan AD, Adler ED, Rozov R, Ge Y, Cohen N, Edelmann LJ, Chang B, Waghray A, Su J, Pardo S, Lichtenbelt KD, Tartaglia M, Gelb BD, Lemischka IR
Title
Patient-specific induced pluripotent stem-cell-derived models of LEOPARD syndrome.
