FaCD Online Syndrome Fact Sheet

Last updated: 05 Jul 2013

Name: Noonan syndrome

Synonym: Male Turner syndrome, Pterygium Colli syndrome, incl. Noonan-like/Multiple Giant Cell Lesion syndrome; Noonan s. with multiple lentigines/LEOPARD syndrome

Mode of Inheritance: AD

Genes

CBL, mapped to 11q23.3
KRAS, mapped to 12p12.1
NRAS, mapped to 1p13.2
PTPN11, mapped to 12q24.1
RAF1, mapped to 3p25
SOS1, mapped to 2p22-p21

Tumor features

juvenile myeloid / myelomonocytic leukemia (JMML)
leukemia, acute lymphoblastic (ALL)
leukemia, acute myeloid (AML, incl. ANLL)
leukemia, chronic lymphocytic (CLL)
leukemia, chronic myelomonocytic (CMML)
myelodysplastic syndrome (MDS)
neuroblastoma, extra-adrenal
rhabdomyosarcoma

Tumor features (possible)

astrocytoma
biliary tract cancer (incl. gallbladder)
brain, cavernous hemangioma
breast cancer
colorectal cancer
ganglioneuroma(tosis)
granular cell tumor, subcutaneous
hepatoblastoma
Hodgkin disease (Hodgkin's lymphoma)
jaw, giant cell granuloma of the
juvenile papillomatosis of the breast
malignant peripheral nerve sheath tumor (= neurofibrosarcoma, malignant schwannoma)
medulloblastoma
non-seminoma
pheochromocytoma
schwannoma (neurilemmoma), peripheral nerve
scrotum, granular cell tumor of the
seminoma
testicular Sertoli-Leydig cell tumor
Wilms' tumor (nephroblastoma)

Non-tumor features

café au lait spots
cubitus valgus
developmental delay/mental deficiency/mental retardation
ears, low-set
epicanthal folds
heart, congenital defect
keratoconus
lip, full upper-
nasal bridge, depressed
neck, webbed
palpebral fissures, downward slanting
pectus excavatum/carinatum
short stature
skeletal anomalies
strabismus

Comment

Characteristic findings in patients with Noonan syndrome are the facial anomalies: hypertelorism, down-slanting palpebral fissures, high-arched eyebrows, epicanthal folds, full upper-lip, depressed nasal root with a wide nasal base and low-set ears with thickened helices; webbed neck, the skeletal anomalies with short stature, pectus excavatum and cubitus valgus; congenital heart disease (pulmonary valve stenosis is most common), abnormalities in the lymphatic system (e.g. lymphedematous legs and probably also the cause of the neck webbing), and mild mental retardation. LEOPARD syndrome is now regarded as being part of Noonan syndrome.

Several malignancies have been reported in this disorder [for a review, see: 30 and 37], most commonly myeloproliferative disorders[1,2,10-16]: mainly chronic myeolomonocytic leukemia / juvenile myelomonocytic leukemia (JMML) and acute lymphoblastic leukemia. JMML in NS carries a relatively benign course. Other tumors reported in Noonan syndrome are central giant cell granuloma of the right maxillary sinus[3], cavernous hemangioma of the brain[4], astrocytoma [31,32] rhabdomyosarcoma[17,28,34], malignant schwannoma[27], pheochromocytoma[28], medulloblastoma [38], ganglioneuroma, intracranial chondroma[9], hepatoblastoma[8], juvenile papillomatosis of the male breast[16], granular cell tumor of the scrotum[19] and multiple subcutaneously[33,34], Hodgkin disease[20] and neuroblastoma[21,23,24], seminoma[25] and non-seminoma testis[26], Sertoli cell tumor of the testis[34] and Wilms tumor[30].

Swanson et al[22] observed that SOS1 is not a significant human oncogene in most cancers, and suggested that Noonan syndrome patients with SOS1 mutations may not be at increased risk of developing cancer. However, some tumors have been reported in these patients[34]: embryonal rhabdomyosarcoma, Sertoli cell testis tumor, granular cell tumors of the skin and a lesion suggestive for a giant cell tumor. De Philippi et al[29] reported a child with a germline NRAS mutation, JMML and dysmorphic feature that did not meet the Noonan syndrome clinical criteria. JMML and Noonan-like features have been observed in patients with germline CBL gene mutations [35,36]

Some patients with neurofibromatosis type 1 (NF1) have facial features resembling those of Noonan syndrome patients. Probably most are to be regarded as a having variant of NF1, associated with germline NF1 gene mutations[18]. As in Noonan syndrome, ALL has been reported in patients with the NF-Noonan disorder[7]. LEOPARD syndrome is now regarded to be part of Noonan syndrome.

Links

Noonan Support Group (TNSSG) 23 1 08

References

[1] Bader-Meunier B, Tchernia G, Mielot F, Fontaine JL, Thomas C, Lyonnet S, Lavergne JM, Dommergues JP. Occurrence of myeloproliferative disorder in patients with Noonan syndrome. J Pediat 130[6], 885-889. 1997.
[2] Choong K, Zipursky A, Taylor G, Freedman M, Kelly E, Chitayat D. Noonan syndrome associated with juvenile chronic myelocytic leukemia: a coincidence or predisposition. Am J Hum Genet 63[4 suppl], A100. 1998.
[3] Ucar B, Okten A, Mocan H, Ercin C. Noonan syndrome associated with central giant cell granuloma. Clin Genet 53[5], 411-414. 1998.
[4] Tanaka Y, Masuno M, Iwamoto H, Aida N, Ijiri R, Yamanaka S, Imaizumi K, Kuroki Y. Noonan syndrome and cavernous hemangioma of the brain. Am J Med Genet 82, 212-214. 1999.
[5] Piombo M, Rosanda C, Pasino M, Marasini M, Cerruti P, Comelli A. Acute lymphoblastic leukemia in Noonan syndrome: report of two cases [see comments]. Med Pediatr Oncol 1993; 21:454-455.
[6] Attard-Montalto SP, Kingston JE, Eden T. Noonan's syndrome and acute lymphoblastic leukaemia. Med Pediatr Oncol 1994; 23:391-392.
[7] Klopfenstein KJ, Sommer A, Ruymann FB. Neurofibromatosis-Noonan syndrome and acute lymphoblastic leukemia: a report of two cases. J Pediatr Hematol Oncol 1999; 21(2):158-160.
[8] Yoshida R, Ogata T, Masawa N, Nagai T. Hepatoblastoma in a Noonan syndrome patient with a PTPN11 mutation. Pediatric blood & cancer 2008; .
[9] Delgado-López PD, Martín-Velasco V, Galacho-Harriero AM, Castilla-Díez JM, Rodríguez-Salazar A, Echevarría-Iturbe C. Large chondroma of the dural convexity in a patient with Noonan's syndrome. Case report and review of the literature. Neurocirugía (Asturias, Spain) 2007; 18(3):241-6.
[10] Cheong JL, Moorkamp MH. Respiratory failure, juvenile myelomonocytic leukemia, and neonatal Noonan syndrome. Journal of pediatric hematology/oncology : official journal of the American Society of Pediatric Hematology/Oncology 2007; 29(4):262-4.
[11] Karow A, Steinemann D, Göhring G, Hasle H, Greiner J, Harila-Saari A, Flotho C, Zenker M, Schlegelberger B, Niemeyer CM, Kratz CP. Clonal duplication of a germline PTPN11 mutation due to acquired uniparental disomy in acute lymphoblastic leukemia blasts from a patient with Noonan syndrome. Leukemia 2007; 21(6):1303-5.
[12] Roti G, La Starza R, Ballanti S, Crescenzi B, Romoli S, Foá R, Tartaglia M, Aversa F, Fabrizio Martelli M, Mecucci C. Acute lymphoblastic leukaemia in Noonan syndrome. British journal of haematology 2006; 133(4):448-50.
[13] Giovannini L, Cavé H, Ferrero-Vacher C, Boutte P, Sirvent N. A new PTPN11 mutation in juvenile myelomonocytic leukaemia associated with Noonan syndrome. Acta paediatrica 2005; 94(5):636-7.
[14] Matsubara K, Yabe H, Ogata T, Yoshida R, Fukaya T. Acute myeloid leukemia in an adult Noonan syndrome patient with PTPN11 mutation. American journal of hematology 2005; 79(2):171-2.
[15] Yoshida R, Miyata M, Nagai T, Yamazaki T, Ogata T. A 3-bp deletion mutation of PTPN11 in an infant with severe Noonan syndrome including hydrops fetalis and juvenile myelomonocytic leukemia. American journal of medical genetics. Part A 2004; 128(1):63-6.
[16] Pacilli M, Sebire NJ, Thambapillai E, Pierro A. Juvenile papillomatosis of the breast in a male infant with Noonan syndrome, café au lait spots, and family history of breast carcinoma. Pediatric blood & cancer 2005; 45(7):991-3.
[17] Jung A, Bechthold S, Pfluger T, Renner C, Ehrt O. Orbital rhabdomyosarcoma in Noonan syndrome. Journal of pediatric hematology/oncology 2003; 25(4):330-2.
[18] Hüffmeier U, Zenker M, Hoyer J, Fahsold R, Rauch A. A variable combination of features of Noonan syndrome and neurofibromatosis type I are caused by mutations in the NF1 gene. American journal of medical genetics. Part A 2006; 140(24):2749-56.
[19] Sidwell RU, Rouse P, Owen RA, Green JS. Granular cell tumor of the scrotum in a child with Noonan syndrome. Pediatric dermatology 2008 May-Jun; 25(3):341-3.
[20] Lo FS, Kuo TT, Wang CJ, Kuo MT, Kuo MC. Hodgkin's lymphoma in a patient with Noonan syndrome with germ-line PTPN11 mutations. International journal of hematology 2008; epub ahead of print .
[21] Mutesa L, Pierquin G, Janin N, Segers K, Thomée C, Provenzi M, Bours V. Germline PTPN11 missense mutation in a case of Noonan syndrome associated with mediastinal and retroperitoneal neuroblastic tumors. Cancer genetics and cytogenetics 2008; 182(1):40-2.
[22] Swanson KD, Winter JM, Reis M, Bentires-Alj M, Greulich H, Grewal R, Hruban RH, Yeo CJ, Yassin Y, Iartchouk O, Montgomery K, Whitman SP, Caligiuri MA, Loh ML, Gilliland DG, Look AT, Kucherlapati R, Kern SE, Meyerson M, Neel BG. SOS1 mutations are rare in human malignancies: implications for Noonan Syndrome patients. Genes, chromosomes & cancer 2008; 47(3):253-9.
[23] Lopez-Miranda B, Westra SJ, Yazdani S, Boechat MI. Noonan syndrome associated with neuroblastoma: a case report. Pediatric radiology 1997; 27(4):324-6.
[24] Ijiri R, Tanaka Y, Keisuke K, Masuno M, Imaizumi K. A case of Noonan's syndrome with possible associated neuroblastoma. Pediatric radiology 2000; 30(6):432-3.
[25] Aggarwal A, Krishnan J, Kwart A, Perry D. Noonan's syndrome and seminoma of undescended testicle. Southern medical journal 2001; 94(4):432-4.
[26] Sriram K, Thomas K, Barnes R. Noonan's syndrome. With carcinoma of undescended testis. IMJ. Illinois medical journal 1987; 171(5):294-6.
[27] Kaplan MS, Opitz JM, Gosset FR. Noonan's syndrome. A case with elevated serum alkaline phosphatase levels and malignant schwannoma of the left forearm. American journal of diseases of children 1968; 116(4):359-66.
[28] Moschovi M, Touliatou V, Vassiliki T, Papadopoulou A, Anna P, Mayakou MA, Maria-Alexandra M, Nikolaidou-Karpathiou P, Polyxeni NK, Kitsiou-Tzeli S, Sophia KT. Rhabdomyosarcoma in a patient with Noonan syndrome phenotype and review of the literature. Journal of pediatric hematology/oncology 2007; 29(5):341-4.
[29] De Filippi P, Zecca M, Lisini D, Rosti V, Cagioni C, Carlo-Stella C, Radi O, Veggiotti P, Mastronuzzi A, Acquaviva A, D'Ambrosio A, Locatelli F, Danesino C. Germ-line mutation of the NRAS gene may be responsible for the development of juvenile myelomonocytic leukaemia. Br J Haematol. 2009 Dec;147(5):706-9
[30] Hasle H. Malignant diseases in Noonan syndrome and related disorders. Horm Res. 2009 Dec;72 Suppl 2:8-14.
[31] Fryssira H, Leventopoulos G, Psoni S, Kitsiou-Tzeli S, Stavrianeas N, Kanavakis E. Tumor development in three patients with Noonan syndrome. Eur J Pediatr. 2008 Sep;167(9):1025-31.
[32] Sanford RA, Bowman R, Tomita T, De Leon G, Palka P. A 16-year-old male with Noonan's syndrome develops progressive scoliosis and deteriorating gait. Pediatr Neurosurg. 1999 Jan;30(1):47-52.
[33] Lohmann DR, Gillessen-Kaesbach G. Multiple subcutaneous granular-cell tumours in a patient with Noonan syndrome.Clin Dysmorphol. 2000 Oct;9(4):301-2.
[34] Denayer E, Devriendt K, de Ravel T, Van Buggenhout G, Smeets E, Francois I, Sznajer Y, Craen M, Leventopoulos G, Mutesa L, Vandecasseye W, Massa G, Kayserili H, Sciot R, Fryns JP, Legius E. Tumor spectrum in children with Noonan syndrome and SOS1 or RAF1 mutations. Genes Chromosomes Cancer. 2010 Mar;49(3):242-52.
[35] Martinelli S, De Luca A, Stellacci E, Rossi C, Checquolo S, Lepri F, Caputo V, Silvano M, Buscherini F, Consoli F, Ferrara G, Digilio MC, Cavaliere ML, van Hagen JM, Zampino G, van der Burgt I, Ferrero GB, Mazzanti L, Screpanti I, Yntema HG, Nillesen WM, Savarirayan R, Zenker M, Dallapiccola B, Gelb BD, Tartaglia M. Heterozygous germline mutations in the CBL tumor-suppressor gene cause a Noonan syndrome-like phenotype. Am J Hum Genet. 2010 Aug 13;87(2):250-7.
[36] Niemeyer CM, Kang MW, Shin DH, Furlan I, Erlacher M, Bunin NJ, Bunda S, Finklestein JZ, Sakamoto KM, Gorr TA, Mehta P, Schmid I, Kropshofer G, Corbacioglu S, Lang PJ, Klein C, Schlegel PG, Heinzmann A, Schneider M, Starý J, van den Heuvel-Eibrink MM, Hasle H, Locatelli F, Sakai D, Archambeault S, Chen L, Russell RC, Sybingco SS, Ohh M, Braun BS, Flotho C, Loh ML. Germline CBL mutations cause developmental abnormalities and predispose to juvenile myelomonocytic leukemia. Nat Genet. 2010 Aug 8. [Epub ahead of print]
[37] Kratz CP, Rapisuwon S, Reed H, Hasle H, Rosenberg PS. Cancer in Noonan, Costello, cardiofaciocutaneous and LEOPARD syndromes. Am J Med Genet C Semin Med Genet. 2011 Apr 15.[Epub ahead of print].
[38] Rankin J, Short J, Turnpenny P, Castle B, Hanemann CO. Medulloblastoma in a patient with the PTPN11 p.Thr468Met mutation.Am J Med Genet A. 2013 Jun 27. doi: 10.1002/ajmg.a.36005. [Epub ahead of print]