Noonan, syndrome

[MIM 163 950, 605 275, 609 942, 611 553, 613 224, 613 563, 613 706]

Prevalence: 1/1,000 to 1/2500. Autosomal dominant transmission with variable penetrance of a mutation in the chain of RAS-MAPK reactions, an important route of transmission of extracellular signals (hormonal etc) to the nucleus influencing cell proliferation and differentiation as well as metabolism. It is a multisystemic disease. A mutation in one of 8 genes located on 12q24.1 and coding for proteins of the RAS-MAPK pathway can cause Noonan or similar (LEOPARD, Costello and cardio-facio-cutaneous) syndrome, grouped under the name of RASopathies (see this term).

Association of:

facial dysmorphism:

- low implanted and posteriorly rotated ears, with a thick helix

- epicanthus and blue-gray or blue-green colored iris with arched eyebrows, palpebral ptosis

- micrognathia (50 %)

- evolution of the facial dysmorphism according to age:

age	front/side	eyes	nose	mouth	neck
newborn	high forehead	hypertelorism epicanthus downslanting palpebra fissures	short and thick, upturned tip, wide base	very marked philtrum, micrognathia	excess nuchal skin
infant	large head, high and prominent forehead	hypertelorism, ptosis	short and wide, depressed base	same	same
child	elongated face , coarse features	same	high and fine crest	same	same
teenager	myopathic facies.	same	important nasolabial folds	same	pterygium coli (webbing)
adult	less typical features, looking thin-looking and transparent skin	same	same	same	same

low hairline in the neck; curly hair that can easily be pulled out
pterygium coli,
thorax with widely spaced nipples and increased angle of Louis causing inferior pectus excavatum and superior pectus carinatum
scoliosis or other spinal abnormalities (30 %)
cardiovascular abnormalities: on the right side of the heart in 50 % of cases: stenosis of the pulmonary artery and its branches (25 %), ASD, VSD, tetralogy of Fallot; hypertrophic cardiomyopathy (20 %) of variable evolution.
cerebrovascular anomalies: arteriovenous malformation, Moyamoya (see this term)
risk of Arnold-Chiari syndrome beyond childhood due to a progressive enlargement of the cerebellum
short stature, cryptorchidism, delayed puberty (sometimes growth hormone deficiency)
hearing problems (20 %)
problems of hemostasis: thrombocytopenia, decrease in the platelet aggregability, factor XI deficiency, rarely factor VII deficiency (corrected by oral administration of vitamin K), sometimes abnormal acquired type von Willebrand disease (valvular stenosis)
lymphatic abnormalities: cutaneous lymphedema at birth, lymphangiectasies, chylous effusion, sometimes plastic bronchitis
normal intelligence or mild mental retardation (learning disabilities and speech), alexithymia (difficulty to verbally express emotions)
pigmentar anomalies: multiple cafe au lait spots, pigmented nevus spots, lentigines
high risk of cancer: lymphoblastic or myeloblastic leukemia, rhabdomyosarcomas

At birth: hypotonia, severe feeding difficulties.

Genotype/phenotype correlation

Gene	heart	size	development	skin/hair	other
PTPN11 (50%)	mainly pulmonary stenosis, less often ASD and cardiomyopathy	short stature	some mutations lead to little or no cognitive impairment		problems of hemostasis and leukemia
SOS1 (10%)	decreased risk of ASD	less risk of short stature	decreased risk of mental retardation	more nevi, lentigines and cafe au lait spots	rhythm disorders
RAFT1 (10 %)	mainly hypertrophic cardiomyopathy	same	same	more nevi, lentigines and cafe au lait spots
KRAS (< 2%)	same	same	severe cognitive deficit
NRAS (< 1%)	same	same	same
BRAF		short stature		more nevi, lentigines and cafe au lait spots	dolichocephaly

Anesthetic implications:

recent cardiac check-up and management according to the cardiac problem; check (including platelets count and function) hemostasis and blood count. Possible difficult intubation. Difficult venous access. One case of narrow lumbar canal has been reported. Avoid low blood pressure and ensure normoventilation given the possible cerebrovascular abnormalities. In teenagers, verify the absence of an Arnold-Chiari syndrome (see this term)

References :

Campbell AM, Bousfield JD.
Anaesthesia in a patient with Noonan's syndrome and cardiomyopathy.
Anaesthesia 1992; 47:131-3.
Schwartz N, Eisenkraft JB.
Anesthetic management of a child with Noonan's syndrome and idiopathic hypertrophic subaortic stenosis.
Anesth Analg 1992; 74:464-6.
Roberts AE, Allanson JE, Tartaglia M, Gelb BD.
Noonan syndrome.
Lancet 2013 ; 381 : 333-42.
Artoni A, Selicorni A, Passamonti SM, Lecchi A, Bucciarelli P, Cerruti M, Cianci P, Gianniello F, Martinelli I.
Hemostatic abnormalities in Noonan syndrome.
Pediatrics 2014 ; 133 : e1299-1304.
Verloes A, Cave H.
Syndrome de Noonan et RASopathies apparentées,
In Syndromes dysmorphiques, édité par D Lacombe et N Philip, Série Progrès en Pédiatrie, Doin 2013, p 13-26.
Jagtap SR, Iher HR, Bakhshi RG, Lahoti HN.
Post-operative airway obstruction in Noonan syndrome: an unusual presentation.
Indian J Anaesth 2015; 59: 442-4
Follansbee CW, Malloy-Walton L.
Ventricular fibrillation due to a likely pathogenic S0S1 variant: An unrecognized etiology of infantile sudden death?
HeartRhythm Case Reports, 2021; 7 (8): 510 DOi: 10.1016/j.hrcr.2021.06.010
Couser DF, Veneziano GC, Nafiu OO, Tobias JD, Beltran RJ.
Use of a spinal-caudal epidural technique for abdominal surgery in a newborn with Noonan syndrome and severe hypertrophic cardiomyopathy.
A&A Practice 2022�; 16e01611

Updated: August 2022