Table 1.
Clinical Features and Genotype of Individuals with RRAS2 Variants
| Subject 1 | Subject 2 |
Family 3 |
Subject 4 | Subject 5 | Subject 6 | ||||
|---|---|---|---|---|---|---|---|---|---|
| 3-II-1 | 3-II-2 | 3-III-1 | 3-III-2 | ||||||
| Origin | Algerian | Sri Lanka | German | Indian | Serbian | South American/ Ashkenazi | |||
| Gender | M | M | F | F | F | M | M | F | M |
| Age at last visit | 7 y 11 m | 12 y 2 m | 32 y | 40 y | 7 y 1 m | 1 y 7 m | 2 weeks | 8 y 10 m | 22 m (last measurement 18 m) |
| RRAS2 variant | c.65_73dup (p.Gly22_Gly24dup) | c.68G>T (p.Gly23Val) | c.208G>A (p.Ala70Thr) | c.208G>A (p.Ala70Thr) | c.208G>A (p.Ala70Thr) | c.208G>A (p.Ala70Thr) | c.215A>T (p.Gln72Leu) | c.208G>A (p.Ala70Thr) | c.70_78dup (p.Gly24_Gly26dup) |
| Inheritance | de novo | de novo | presumed paternal | presumed paternal | maternal | maternal | de novo | de novo | de novo |
| Prenatal features | NE, PH | PH | NA | NA | NA | N | NE, fetal ventriculo-megaly and cardiac abnormalities | NE | PH, LGA |
| Birth measurements: weight, length, OFC (weeks GA) | 3,730 g, 50.5 cm, 37 cm (35) | 3,180 g, 46.5 cm, 35 cm (35) | NA | 3,740 g, 51 cm, 36 cm | 3,110 g, 48 cm, 36 cm (39) | 2,440 g, 48 cm, 32 cm (35) | 2,400 g (33) | NA | 3,600 g, 51 cm, 38 cm (35) |
| Feeding difficulties | PF | PF, TF | NA | NA | PF | N | NA | N | N |
| Height at last examination | 125.5 cm (+0.3 SD) | 139.5 (−1.5 SD) 85 cm (−3.3 SD)a | 160 cm (−1.3 SD) | 170 cm (+0.3 SD) | 108 cm (−3.0 SD) | 78 cm (−1.8 SD) | NA | 122 cm (−2.1 SD) | 84.5 cm (+0.5 SD) |
| Weight | 27.5 kg (+0.5 SD) | 32.5 kg (−1.4 SD) | NA | 59 kg (+0.1 SD) | 18.6 kg (−1.8 SD) | 11 kg (−0.4 SD) | NA | 22 kg (−1.9 SD) | 12.5 kg (+0.7 SD) |
| OFC | 54 cm (+1.2 SD) | 57 cm (+2.5 SD) | 52.5 cm (−2.2 SD) | 55.5 cm (+0.2 SD) | 52 cm (+0.4 SD) | 49 cm (+0.2 SD) | NA | 52.5 cm (+0.2 SD) | 54.5 cm (+5.0 SD) |
| Cryptorchidism | N | N | NA | NA | NA | N | hypoplastic scrotum | NA | N |
| Congenital heart defect | SVAoS | VSD | VSD | N | N | N | TOF | AVSD, multiple VSDs | N |
| Lymphatic anomalies | N | N | N | N | N | N | N | N | N |
| Facial anomalies | typical NS | typical NS | suggestive NS | very mild in adulthood | typical NS | typical NS | multiple anomalies | suggestive NS | typical NS |
| Development | N | mild MD, mild LD | N | N | mild MD, mild LD | N | NA | N | mild global delay |
| Neurology | N | Chiari malformation | N | N | N | N | non-obstructive hydrocephalus | N | mild ventriculomegaly, hypotonia |
| Skeletal | N | N | N | N | N | N | 11 rib pairs, proximally placed thumb, spinal canal stenosis | pectus excavatum | N |
| Hematology & oncology | N | lymphopenia | N | N | N | N | thrombocytopenia | N | N |
| Skin and hair | glabellar heamangioma | N | N | N | atopic dermatitis, | N | N | N | glabellar hemangioma |
| Ocular | N | strabismus | N | strabismus | hyperopia, bilateral ptosis | N | NA | N | strabismic amblyopia, esotropia |
| Other malformations/anomalies | N | GH deficiency, GH treatment from age 4 y | unilateral duplex kidney | N | multiple allergies, bronchitis | N | labyrinth dysplasia, anteriorly placed anus | minor hippocampal malformation on brain MRI | N |
Abbreviations: AVSD, atrioventricular septal defect; F, female; GA, gestational age; GD, global delay; GH, growth hormone; LD, learning difficulties; LGA, large for gestational age; M, male; m, months; MD, motor delay; N, none/normal; NA, not applicable/not available; NE, nuchal edema; OFC, occipitofrontal head circumference; PF, poor feeding reported; PH, polyhydramnios; SVAoS, supravalvular aortic stenosis; TF, tube feeding (>4 weeks); TOF, Tetralogy of Fallot; y, years.
a
Before onset of growth hormone treatment at age 3 y 6 m.