Table 2 Clinical features of the patients with pathogenic or likely pathogenic variants
Patient | Patients with pathogenic or likely pathogenic variants in the responsible genes for SRS | Patients with pathogenic variants in causative genes for known genetic syndromes presenting with growth failure | |||||||
|---|---|---|---|---|---|---|---|---|---|
Patient 1 [12] | Patient 2 [12] | Patient 3 | Patient 4 | Patient 5 | Patient 6 | Patient 7 | Patient 8 | Patient 9 | |
Genetic diagnosis | SRS | SRS | SRS | SRS | IGF1R abnormality | SHORT syndrome | Floating-Harbor syndrome | Pitt-Hopkins syndrome | Noonan syndrome |
Gene | IGF2 | IGF2 | CDKN1C | PLAG1 | IGF1R | PIK3R1 | SRCAP | TCF4 | PTPN11 |
Variant | p.(Cys70Tyr) | p.(Cys71Arg) | p.(Arg316Gln) | p.(Arg197*) | p.(Ser487Profs*21) | p.(Arg631Gln) | p.(Pro2459Leufs*16) | p.(Gln368Glyfs*6) | p.(Ile282Val) |
Sex | Male | Male | Female | Female | Male | Male | Male | Female | Male |
Age at the last examination (years) | 8 | 15 | 12 | 12 | 3 | 3 | 12 | 12 | 13 |
Gestational age (weeks:days) | 36:0 | 37:4 | 33:1 | 38:5 | 39:3 | 41:1 | 38:2 | 36:0 | 33:6 |
Birth length in cm (SDS)a | 34.5 (− 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)a | 1164 (− 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)a | 31.0 (− 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,c | 70.9 (− 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 | − 1.94 | 0.44 | − 3.19 | − 1.29 |
Height at the last examination in cm (SDS)b | 108.8 (− 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)b | 14.6 (− 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 treatment | 6 years~ | 7 ~ 15 years | 3 ~ 12 years | 3 ~ 12 years | − | − | 3 years~ | − | 9 years~ |
SGAd | + | + | + | + | + | + | + | + | − |
Postnatal growth failurec,e | + | + | + | + | + | + | + | − | + |
Relative macrocephaly at birthf | + | + | + | + | + | + | + | − | − |
Protruding forehead | + | + | + | + | + | + | − | + | + |
Body asymmetry | − | + | − | − | − | − | − | − | − |
Feeding difficulties and/or low BMI | + | + | − | + | + | − | − | + | + |
NH-CSS | 5/6 | 6/6 | 4/6 | 5/6 | 5/6 | 4/6 | 3/6 | 3/6 | 3/6 |
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 levels | SGA, postnatal growth failure, protruding forehead, triangular face, micrognathia, dental delay, low-set ears | SGA, postnatal growth failure, relative macrocephaly, triangular face, delayed bone age in early childhood, speech delay, bulbous nose, broad fingertips | Narrow 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 | Â | Â | Â | Â | Microcephaly, pectus excavatum, developmental delay | Lipoatrophy, inguinal hernia, deep-set eyes, Rieger abnormality, hyperextensibility of joints, speech delay, sensorineural deafness | Long eyelashes, deep-set eyes, short philtrum | Myopia, constipation, unstable gait | Pulmonary valve stenosis, hypertrophic cardiomyopathy, lymphedema, disordered bleeding, cryptorchidism, down-slanting of palpebral fissures, ptosis, low-set ears, low posterior hairline, webbed neck |
Development | Â | Â | Â | Â | Â | Â | Â | Â | Â |
 Motor developmental delay | + | + | − | − | − | − | − | + | − |
  Age at head control (months) | 5 | 6 | 4 | 4 | 4 | 4 | Unknown | 12 | 4 |
  Age at sitting without support (years) | 1.0 | 0.8 | 0.6 | 0.7 | 0.5 | 0.7 | Unknown | Unknown | 0.8 |
  Age at walking without support (years) | 1.5 | 1.3 | 1.0 | 1.0 | 1.3 | 1.3 | Unknown | 4.8 | 1.1 |
 Speech delay | + | + | − | − | − | − | + | + | − |
 IQ/DQ (age at examination) | 77 (3 years) | 79 (6 years) | Unknown | Unknown | NE | NE | Unknown | 17 (6 years) | NE |
Other features | Cleft palate, hypospadias, bifid scrotum, hypoplastic finger nails | Cleft palate, hypospadias, syndactyly | Left inguinal hernia, café au lait spot, Mongolian spot, bronchial asthma, dysmenorrhea | ADHD, hypothyroidism (5 years~) | − | − | Perthes disease, hematoma in the left temporal lobe, atopic dermatitis | − | − |
Paternal height in cm (SDS) | Unknown | 169 (− 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) |