Table 1

Clinical features of patients with KRAS mutations

	Patient No 1	Patient No 2	Patient No 3	Patient No 4	Patient No 5	Patient No 6
KRAS mutation*	K5N (c.15A→T)	V14I (c.40G→A)	Q22E (c.64C→G)	Q22R (c.65A→G)	P34L (c.101C→T)	P34Q (c.101C→A)
Age at last follow up	7.5 months	16 years	2 years	3.3 years	17 years	3.4 years
Sex	Male	Male	Male	Female	Male	Male
Birth weight (g)†	3195	4000	3400	2820	4470	3060
Congenital heart defect	Pst	No	Pst	Pst	No	Pst
Facial features	Hypertelorism, downslanting palpebral fissures, coarse face, anteverted nostrils, low-set dysplastic ears	Hypertelorism, low-set ears	Hypertelorism, downslanting palpebral fissures, anteverted nostrils, low-set ears	Hypertelorism, downslanting palpebral fissures, low-set ears	Hypertelorism, downslanting palpebral fissures	Hypertelorism, low set ears, flat nasal bridge, posteriorly rotated ears
Stature	<1st centile	1st centile	15th centile	3rd–10th centile	1st centile	<1st centile
Relative macrocephaly	Yes	Yes	No	Yes	Yes	No
Short/webbed neck	Webbed neck	Short neck	Short and webbed neck	Short and webbed neck	Short neck	Webbed neck
Thorax deformity	Pectus carinatum	Mild pectus excavatum	No	Broad chest, mild pectus excavatum	Pectus excavatum (op)	No
Cryptorchidism	No	No	No	–	No	No
Ophthalmological problems	Ptosis, strabismus, nystagmus	Ptosis (op), strabismus	Ptosis	Ptosis, strabismus	Strabismus	Mild ptosis
Developmental delay/mental retardation	Moderate	Mild	Moderate	Moderate	Mild	Mild
Abnormal hair	Sparse	No, sparse hair in early childhood	Thin hair, sparse eyebrows	No	No	No
Skin abnormalities	Redundant skin, deep palmar and plantar creases	No	Deep palmar and plantar creases	No	No	No
Other	Macroglossia, severe feeding difficulties and failure to thrive	Seizures, mild hydrocephalus internus, cubitus valgus	Unilateral pyelectasia, failure to thrive	–	Received GH treatment	Failure to thrive and feeding problems in infancy
Clinical diagnosis	CS	NS	CFC	Severe NS	NS	NS

	Patient No 7	Patient No 8	Patient No 9	Patient No 10	Patient No 11	Patient No 12
ASD, atrial septal defect; CFC, cardio-facio-cutaneous syndrome; CS, Costello syndrome; GH, growth hormone; H(O)CM, hypertrophic (obstructive) cardiomyopathy; MR, mental retardation; nd, not documented; NS, Noonan syndrome; op, operated; Pst, pulmonic stenosis.
*Novel mutations are in bold.
†All children were born at term.
‡Died from unexplained sudden death at 14 months of age.
KRAS mutation*	I36M (c.108A→G)	G60R (c.178G→C)	D153V (isoform B) (c.460A→T)	D153V (isoform B) (c.460A→T)	F156I (isoform B) (c.466T→A)	F156L (isoform B) (c.468C→G)
Age at last follow-up	17 years	5 years	20 years	5.5 years	8.5 years	14 months‡
Sex	Female	Female	Male	Male	Male	Male
Birth weight (g)†	3000	3350	3210	2820	4850	3090
Congenital heart defect	ASD	HOCM	No	Pst	No	HCM, Pst, ASD
Facial features	Hypertelorism, downslanting palpebral fissures, posteriorly rotated ears	Hypertelorism, downslanting palpebral fissures, coarse face, low-set ears	Hypertelorism, downslanting palpebral fissures, posteriorly rotated ears	Hypertelorism, anteverted nostrils, low-set ears	Hypertelorism, prominent forehead, bitemporal narrowing, epicanthic folds, downslanting palpebral fissures, ptosis, widely spaced teeth, low-set ears	Hypertelorism, coarse face, anteverted nostrils, low-set dysplastic ears
Stature	3rd centile	<1st centile	10th centile	<1st centile	3rd centile	<3rd centile
Relative macrocephaly	Yes	No	Yes	Yes	Yes	Yes
Short/webbed neck	Short and webbed neck	Short neck	Short and webbed neck	Short neck	Short and webbed neck	Short and webbed neck
Thorax deformity	Pectus excavatum	No	Pectus excavatum	Pectus excavatum	Pectus excavatum	No
Cryptorchidism	–	–	Yes	No	No	Yes
Ophthalmological problems	Mild ptosis	No	Ptosis	Mild ptosis, strabismus	Ptosis, nystagmus, strabismus	Ptosis
Developmental delay/mental retardation	Mild	Moderate	Mild	Mild	Moderate	Moderate
Abnormal hair	Thin hair	Thin and sparse hair	No	No	Low posterior hair line, sparse hair at early age	Sparse
Skin abnormalities	Loose/redundant skin in early childhood	No	No	No	Wrinkled skin of palms and soles	Loose/redundant and soft skin with deep palmar and plantar creases
Other	Received GH treatment, facial asymmetry, bleeding diathesis	Feeding difficulties and failure to thrive	–	Haemangioma of lower lip, vascular malformation of the brain, brachydactyly, GH treatment	Hearing loss, widely spaced nipples, inguinal hernia, muscular hypotonia	Dandy-Walker malformation, laryngomalacia, conductive hearing deficits, severe feeding difficulties and failure to thrive
Clinical diagnosis	NS	CFC	NS	NS	NS/CFC	CS