All known patients with germline or mosaic RNase III domain hotspot mutations
| DICER1 syndrome+phenotype | Klein et al
5
Pat 1 | Klein et al. Pat 25 | Pontén et al (the present study)r | Carlens et al 10 | de Kock et al. 6
Pat 1 (Brenneman et al 11 Pat 102) | de Kock et al 6
Pat 2 (Brenneman et al 11 Pat 105) | de Kock et al
6
Pat 3 | de Kock et al 6
Pat 4 Brenneman et al 11 Pat 120) | de Kock et al
7
Pat 12 | Brenneman et al 11
Pat 101 | Brenneman et al 11
Pat 103 | Brenneman et al.11
Pat 104 | Brenneman et al
11
Pat 123 |
| Patient age and sex (,if reported) | 5 y M | 14 m M | 18 y M | 6 y F | 10.9 y M | 17.2 y F | 6.8 y F | 4.1 y M | 21 m M | 9 y | 14 y | 13 y F | 8 y |
| DICER1 RNase III hotspot mutation: domain/germline or mosaic | c.5138A>T p.D1713V RNase IIIb domain mosaic | c.5125G>T p.D1709Y RNase IIIb domain mosaic | c.4031C>T p.S1344L RNase IIIa domain germline | c.4031C>T p.S1344L RNase IIIa domain germline | c.5125G>A p.D1709N RNase IIIb domain mosaic | c.5437G>C p.E1813Q RNase IIIb domain mosaic | c.5439G>C p.E1813D RNase IIIb domain mosaic | c.5425G>A p.G1809R RNase IIIb domain mosaic | c.5125G>C p.D1709H RNase IIIb domain germline | c.5126A>G; p.D1709G RNase IIIb domain mosaic | c.5125G>A; p.D1709N RNase IIIb domain mosaic | c.5428G>T; p.D1810Y RNase IIIb domain mosaic | c.5113G>A; p.E1705K RNase IIIb domain mosaic |
| DICER1 RNase III hotspot mutation: tissue distribution and VAF | Blood: (21%) Normal kidney: (35%) Wilms tumour:(37%) | Blood: (28%) Normal kidney:(35%) Wilms tumour:(47%) | Blood: (50%) Skin: (50%) Buccal cells: (50%) Saliva: (50%) Kidney tumour: (87%) Lung tumour: (90%) | Blood: (heterozygous) | Blood: (4.6%) Skin: (4.23%–7.13%) Saliva: (2.78%) Normal brain: (11.52%) Lymph node: (0%) NCMH: (17.72%) Type I PPB: (34.24%) Type II PPB: (43.84%) Brain PPB metastasis: (14.97%–51%) | Blood: (0.04%) Urine: (0.4%–0.66%) Saliva: (0.25%–0.27%) Hair: (0.24%) Lung cysts: (0%) Follicular thyroid ca:(66.6%–74.53%) SLCT (right): (76.8%–87.33%) SLCT (left): (31.8%–44.48%) NCMH: (29.3%–30.55%) | Blood: (0–0.04%) Normal right kidney #1: (3.26%–4.75%) Normal right kidney #2: (12.86%–14.55%) CN left kidney: (7.62%) Maldevelopmental lesion right kidney: (56.24%) Juvenile polyps: (38.9%) NCMH: (27.73%) | Blood: (0%–0.2%) Hair: (0.02%) Saliva: (0%–0.04%) Reactive lung (left): (0.35%–1%) Reactive lung (right): (6.93%–7.08%) Type II PPB: (37%–37.84%) | Blood: (heterozygous) Pituitary blastoma: (NR) | Blood: (NR) Normal lymph node: (15.2%) | Blood: (0.28%) CN: (14.9%) Type Ir PPB: (16.2%) Small intestine, polyps: (17.5%) | Blood: (0.21%) Normal Fallopian tube: (7.19%) Type Ir PPB: (27.8%) CN: (29.2%) SLCT (right): (34.2%) SLCT (left): (92.4%) | Blood: (ND) Normal ureter: (13%) Type I PPB:(24%) CN: (35%) |
| DICER1 LOF mutation: tissue distribution/(allele frequency) | Blood: (ND) Normal kidney: (ND) Wilms tumour: c.1304C>A, p.P453H and c.5692A>G p.R1898G (variable) | Blood: (ND) Normal kidney: (ND) Wilms tumour: (ND) | Blood: (ND) Kidney tumour: 0.61 Mb deletion (approx. 50%) | Blood: (ND) | Blood: (ND) PPB metastasis in brain: (allele loss) | Blood: (ND) NCMH: (ND) Thyroid ca: (allele loss) SLCT (right): (allele loss) SLCT (left): c.4626-4626delG; p.Q1542Hfs*18: (21.7%–44.48%) NCMH: c.4458_4458delA p.K1486Nfs*4 (NR) | NCMH: c.4651-4652insTGCT; p.E1551Vfs*7 (NR) | Blood: (ND) Reactive lung: (ND) Type II PPB: c.1966C>T; p.R656* (NR) | Blood: (ND) Pituitary blastoma: (allele loss) | Blood: (ND) Normal Lymph node: (ND) | Blood: (ND) CN: c.1129G>A; p.V377I(3.1%) Type Ir PPB: c.1200G>A; p.W400* (4.1%) Small intestine polyp: c.96G>A; p.W32* (3%) | Blood: (ND) Normal Fallopian tube: (ND) Type Ir PPB: (ND) CN: c.1711delT; p.S571Vfs*16 (21.8%) SLCT (right): c.1775delA; p.K592Mfs*15 (36.2%) SLCT (left): (allele loss) | Blood: (ND) Normal ureter: (ND) Type I PPB: (allele loss) CN: (allele loss) |
| Intellectual impairment | DD | DD | ID | ID | ND | ND | ND | ND | ND | NR | NR | NR | NR |
| Autism | Yes | NR | Yes | Yes | NR | NR | NR | NR | NR | NR | NR | NR | NR |
| Hypotonia | Yes | Yes | Yes | Yes | NR | NR | NR | NR | NR | NR | NR | NR | NR |
| Overgrowth | Macrocephaly/Global | Macrocephaly/Global | Macrocephaly | Macrocephaly | ND | ND | ND | ND | ND | NR | NR | NR | NR |
| Birth weight | 4904 g (>99th percentile) | 2920 g (18th percentile) | 3752 g (79th percentile) | 4430 g (>99th percentile) | NR | NR | NR | NR | NR | NR | NR | NR | NR |
| Birth length | NR | NR | 53 cm (95th percentile) | 56 cm (>99th percentile) | NR | NR | NR | NR | NR | NR | NR | NR | NR |
| OFC at birth | NR | NR | 42 cm (>99th percentile) | 42 cm (>99th percentile) | NR | NR | NR | NR | NR | NR | NR | NR | NR |
| Growth parameters: weight (w)/length (L)/head size (OFC) | 28 m: W 15.5 kg (91.9th percentile) L 95 cm (95.5th percentile) OFC 55 cm (>99th percentile) | 14 m: W 13.5 kg (>99th percentile) L 81 cm (95.6th percentile) OFC 53 cm (>99th percentile) | 18 y: W normal L normal OFC 62 cm (>99th percentile) | 6 y: W 15.8 kg (3.6th percentile) L 112 cm (27.4th percentile) | NR | NR | NR | NR | NR | NR | NR | NR | NR |
| Nephromegaly | Yes | Yes | NR | No | NR | NR | NR | NR | NR | NR | NR | NR | NR |
| Renal cysts | Multiple small cysts | Multiloculated cystic mass (left) | CN at 8 y | NR | NR | Hamartomatous bilat renal cysts at 1 y 1 m | CN at 1 y | NR | Yes | CN at 1 y 3 m | CN at 1 y | CN at 1 y | CN at 1 y 6 m |
| Lung cysts/PPB | Lung cysts/PPB | Lung cysts/PPB | Type I PPB | Lung cysts at 11 m | Type I PPB Type II PPB | Benign multifocal bilat lung cysts at 1 y 1 m | Type I PPB (right) Lung cysts (left) | Lung cysts (right) Type I PPB (left) at 11 m, Type II PPB at 4 y | Type II PPB | PPB at 1 y 3 m | Type Ir PPB at 11 m | Type Ir PPB at 5 m | Type I PPB at 1 y 8 m |
| Hypertelorism | Yes | (Yes) | (Yes) | Yes | NR | NR | NR | NR | NR | NR | NR | NR | NR |
| Prominent forehead | Yes | Yes | Yes | Yes | NR | NR | NR | NR | NR | NR | NR | NR | NR |
| Anteverted nares | Yes | NR | Yes | NR | NR | NR | NR | NR | NR | NR | NR | NR | NR |
| Flat nasal bridge | Yes | Yes | Yes | NR | NR | NR | NR | NR | NR | NR | NR | NR | NR |
| Micrognathia | (Yes) | NR | (Yes) | NR | NR | NR | NR | NR | NR | NR | NR | NR | NR |
| Macrosomia | NR | NR | Yes | Yes | NR | NR | NR | NR | NR | NR | NR | NR | NR |
| Pits | Sacral dimple+dimples on sides of ankles | Ear pit (left) | Ear pits, posterior helix (left) | NR | NR | NR | NR | NR | NR | NR | NR | NR | NR |
| Skin findings | Doughy hands Fat pads on feet Pronounced plantar creases | NR | Soft skin Doughy soft hands Furrowed forehead Multiple nevi | NR | NR | NR | NR | NR | NR | NR | NR | NR | NR |
| Skeletal abnormalities | Pectus excavatum Kyphosis | NR | Scoliosis Polydactyly | Narrow thorax Increased intermammillary distance Prominent sternum | NR | NR | NR | NR | NR | NR | NR | NR | NR |
| Increased CSF space | Yes | Yes | Yes | Yes | NR | NR | NR | NR | NR | NR | NR | NR | NR |
| Fontanel | Large anterior fontanel | NR | Late fontanel closure | NR | NR | NR | NR | NR | NR | NR | NR | NR | NR |
| Hernia | Inguinal and umbilical | Inguinal | Inguinal | NR | NR | NR | NR | NR | NR | NR | NR | NR | NR |
| Brain imaging | Enlarged lateral and third ventricles | Mild volume loss | Mild volume loss Thin corpus callosum Cyst | Enlarged lateral ventricles Hydrocephalus | NR | NR | NR | NR | NR | NR | NR | NR | NR |
| Wilms tumour (age of Dx) | Bilateral 9 m/5 y | Bilateral 1 y 1 m/2 y 6 m | Bilateral 1 y 3 m/1 y 6 m | Unilateral 11 m | ND | ND | ND | ND | ND | ND | ND | ND | ND |
| Small intestine, polyps | NR | NR | NR | NR | Yes | NR | Hamartomatous juvenile intestinal polyps at 6 m | NR | NR | Yes | Yes | Yes | NR |
| Additional cysts or tumours | NR | NR | NR | NCMH at 8 y Testicular cyst at birth PPB brain metastasis | NCMH at 15 y Pineoblastoma at 7 y Follicular papillary thyroid carcinoma at 10 y Bilat SLCT at 13 y and 15 y Ciliary body medulloepithelioma at 17 y | NCMH at 6 y | NR | Pituitary blastoma at 8 m | Hodgkin lymphoma at 7 y | Pelvic sarcoma at 14 y | SLCT bilat at 5 y and 13 y Thyroid nodules at 7 y | NR | |
| Other clinical findings | Respiratory distress | Pre-eclampsia in mother | Reduced fetal movement during pregnancy Retentio testis Rocker bottom feet Language impairment Large teeth Two blood vessels in umbilical cord Pulmonary embolism after scoliosis surgery | Low set ears Pulmonary infections Myopathic facies with ptosis and open mouth | Scrotal web at birth Enteritis cystica profunda at 9 m | Left ocular pre-phtisisical changes, vascular mass Recurrent retinal detachment | Renal medullary malformation with disorganised collecting system and dilated lymphatic vessels | NR | NR | NR | NR | NR | NR |
CN, cystic nephroma; DD, developmental delay; ID, intellectual disability; LOF, loss of function; m, month; NCMH, nasal chondromesenchymal hamartoma; ND, none detected; NR, not reported; OFC, occipital frontal circumference; PPB, pleuropulmonary blastoma; SLCT, Sertoli-Leydig cell tumour; VAF, variant allele frequency; y, year.