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Table 2 Clinical features of the patients with pathogenic or likely pathogenic variants

From: Contribution of gene mutations to Silver-Russell syndrome phenotype: multigene sequencing analysis in 92 etiology-unknown patients

PatientPatients with pathogenic or likely pathogenic variants in the responsible genes for SRSPatients with pathogenic variants in causative genes for known genetic syndromes presenting with growth failure
Patient 1 [12]Patient 2 [12]Patient 3Patient 4Patient 5Patient 6Patient 7Patient 8Patient 9
Genetic diagnosisSRSSRSSRSSRSIGF1R abnormalitySHORT syndromeFloating-Harbor syndromePitt-Hopkins syndromeNoonan syndrome
GeneIGF2IGF2CDKN1CPLAG1IGF1RPIK3R1SRCAPTCF4PTPN11
Variantp.(Cys70Tyr)p.(Cys71Arg)p.(Arg316Gln)p.(Arg197*)p.(Ser487Profs*21)p.(Arg631Gln)p.(Pro2459Leufs*16)p.(Gln368Glyfs*6)p.(Ile282Val)
SexMaleMaleFemaleFemaleMaleMaleMaleFemaleMale
Age at the last examination (years)815121233121213
Gestational age (weeks:days)36:037:433:138:539:341:138:236:033:6
Birth length in cm (SDS)a34.5 (− 3.85)39.0 (− 3.54)38.3 (− 1.95)42.0 (− 3.12)45.0 (− 2.11)47.0 (− 1.65)43.0 (− 2.49)38.0 (− 2.97)45.0 (+ 0.47)
Birth weight in g (SDS)a1164 (− 4.23)1336 (− 4.23)1120 (− 2.85)1804 (− 3.28)2292 (− 2.22)2386 (− 3.01)2332 (− 1.90)1508 (− 2.79)2130 (+ 0.04)
Birth OFC in cm (SDS)a31.0 (− 0.72)30.8 (− 1.49)28.1 (− 1.12)32.0 (− 0.86)32.9 (− 0.28)33.0 (− 0.54)32.0 (− 0.80)28.5 (− 2.28)31.8 (+ 0.68)
Height at 24 months in cm (SDS)b,c70.9 (− 4.63)72.5 (− 4.29)75.1 (− 3.34)77.6 (− 3.42)78.9 (− 2.38)77.9 (− 2.50)79.2 (− 3.37)81.4 (− 1.44)80.7 (− 2.20)
BMI at 24 months (SDS)b,c− 2.70− 1.19− 1.26− 2.76− 2.09− 1.940.44− 3.19− 1.29
Height at the last examination in cm (SDS)b108.8 (− 3.26)141.5 (− 4.68)143.5 (− 1.73)141.6 (− 2.06)87.9 (− 2.03)93.8 (− 1.27)149.2 (− 0.76)134.9 (− 2.33)140.1 (− 3.09)
Weight at the last examination in kg (SDS)b14.6 (− 5.25)30.5 (− 5.81)36.9 (− 1.22)28.0 (− 2.99)11.5 (− 1.79)11.2 (− 2.70)38.6 (− 0.85)28.1 (− 2.17)26.6 (− 4.31)
GH treatment6 years~7 ~ 15 years3 ~ 12 years3 ~ 12 years3 years~9 years~
SGAd++++++++
Postnatal growth failurec,e++++++++
Relative macrocephaly at birthf+++++++
Protruding forehead++++++++
Body asymmetry+
Feeding difficulties and/or low BMI++++++
NH-CSS5/66/64/65/65/64/63/63/63/6
Triangular face++++++++
Fifth finger clinodactyly++++++
Fifth finger brachydactyly+++++++
Present characteristic features of genetic syndrome caused by the pathogenic variant    SGA, postnatal growth failure, feeding difficulties, triangular face, high plasma IGF-1 levelsSGA, postnatal growth failure, protruding forehead, triangular face, micrognathia, dental delay, low-set earsSGA, postnatal growth failure, relative macrocephaly, triangular face, delayed bone age in early childhood, speech delay, bulbous nose, broad fingertipsNarrow forehead, thin lateral eyebrows, wide nasal bridge/ridge/tip, flared nasal alae, full cheeks/prominent midface, wide mouth/full lips/cupid bow upper lip, thickened/overfolded helices, severe developmental delay, breathing regulation anomalies (intermittent hyperventilation, apnea) (10 years~)Postnatal growth failure, triangular face, chest deformity, cubitus valgus, hypertelorism
Absent characteristic features of genetic syndrome caused by the pathogenic variant    Microcephaly, pectus excavatum, developmental delayLipoatrophy, inguinal hernia, deep-set eyes, Rieger abnormality, hyperextensibility of joints, speech delay, sensorineural deafnessLong eyelashes, deep-set eyes, short philtrumMyopia, constipation, unstable gaitPulmonary valve stenosis, hypertrophic cardiomyopathy, lymphedema, disordered bleeding, cryptorchidism, down-slanting of palpebral fissures, ptosis, low-set ears, low posterior hairline, webbed neck
Development         
 Motor developmental delay+++
  Age at head control (months)564444Unknown124
  Age at sitting without support (years)1.00.80.60.70.50.7UnknownUnknown0.8
  Age at walking without support (years)1.51.31.01.01.31.3Unknown4.81.1
 Speech delay++++
 IQ/DQ (age at examination)77 (3 years)79 (6 years)UnknownUnknownNENEUnknown17 (6 years)NE
Other featuresCleft palate, hypospadias, bifid scrotum, hypoplastic finger nailsCleft palate, hypospadias, syndactylyLeft inguinal hernia, café au lait spot, Mongolian spot, bronchial asthma, dysmenorrheaADHD, hypothyroidism (5 years~)Perthes disease, hematoma in the left temporal lobe, atopic dermatitis
Paternal height in cm (SDS)Unknown169 (− 0.31)170 (− 0.14)173 (+ 0.38)166 (− 0.82)170 (− 0.14)174 (+ 0.55)170 (− 0.14)187 (+ 2.78)
Maternal height in cm (SDS)150 (− 1.54)159 (+ 0.17)154 (− 0.78)147 (− 2.11)156 (− 0.40)158 (− 0.02)161 (+ 0.55)156 (− 0.40)167 (+ 1.70)
  1. SRS Silver-Russell syndrome, SDS standard deviation score, OFC occipitofrontal circumference, BMI body mass index, GH growth hormone, SGA small for gestational age, NH-CSS Netchine-Harbison clinical scoring system, IQ intelligence quotient, DQ developmental quotient, NE not examined, ADHD attention-deficit hyperactivity disorder
  2. aBirth length, weight, and OFC were evaluated by the sex- and the gestational age-matched Japanese reference data (http://jspe.umin.jp/medical/chart_dl.html)
  3. b Postnatal height, BMI, and weight were evaluated by the sex- and the age-matched Japanese reference data (http://jspe.umin.jp/medical/chart_dl.html)
  4. cIf we did not get information at 24 ± 1 months, we used the data at the nearest measure available older than 25 months
  5. dBirth length and/or birth weight ≤ − 2 SDS
  6. eHeight at 24 ± 1 months ≤ − 2 SDS or height ≤ − 2 SDS below mid-parental target height. Mid-parental target height was calculated as follows: ((father’s height + mother’s height)/2) + 6.5 cm for boys and − 6.5 cm for girls.
  7. fHead circumference at birth ≥ 1.5 SDS above birth length and/or weight SDS