Table 1

All known patients with germline or mosaic RNase III domain hotspot mutations

DICER1 syndrome+phenotypeKlein et al5
Pat 1
Klein et al.
Pat 25
Pontén et al (the present study)rCarlens et al10de Kock et al. 6
Pat 1
(Brenneman et al11 Pat 102)
de Kock et al 6
Pat 2
(Brenneman et al11 Pat 105)
de Kock et al6
Pat 3
de Kock et al 6
Pat 4
Brenneman et al11 Pat 120)
de Kock et al7
Pat 12
Brenneman et al 11
Pat 101
Brenneman et al 11
Pat 103
Brenneman et al.11
Pat 104
Brenneman et al11
Pat 123
Patient age and sex (,if reported)5 y M14 m M18 y M6 y F10.9 y M17.2 y F6.8 y F4.1 y M21 m M9 y14 y13 y F8 y
DICER1 RNase III hotspot mutation: domain/germline or mosaicc.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 VAFBlood: (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 impairmentDDDDIDIDNDNDNDNDNDNRNRNRNR
AutismYesNRYesYesNRNRNRNRNRNRNRNRNR
HypotoniaYesYesYesYesNRNRNRNRNRNRNRNRNR
OvergrowthMacrocephaly/GlobalMacrocephaly/GlobalMacrocephalyMacrocephalyNDNDNDNDNDNRNRNRNR
Birth weight4904 g (>99th percentile)2920 g (18th percentile)3752 g (79th percentile)4430 g (>99th percentile)NRNRNRNRNRNRNRNRNR
Birth lengthNRNR53 cm (95th percentile)56 cm (>99th percentile)NRNRNRNRNRNRNRNRNR
OFC at birthNRNR42 cm (>99th percentile)42 cm (>99th percentile)NRNRNRNRNRNRNRNRNR
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)
NRNRNRNRNRNRNRNRNR
NephromegalyYesYesNRNoNRNRNRNRNRNRNRNRNR
Renal cystsMultiple small cystsMultiloculated cystic mass (left)CN at 8 yNRNRHamartomatous bilat renal cysts at 1 y 1 mCN at 1 yNRYesCN at 1 y 3 mCN at 1 yCN at 1 yCN at 1 y 6 m
Lung cysts/PPBLung cysts/PPBLung cysts/PPBType I PPBLung cysts at 11 mType I PPB
Type II PPB
Benign multifocal bilat lung cysts at 1 y 1 mType I PPB (right)
Lung cysts (left)
Lung cysts (right)
Type I PPB (left) at 11 m, Type II PPB at 4 y
Type II PPBPPB at 1 y 3 mType Ir PPB at 11 mType Ir PPB at 5 mType I PPB at 1 y 8 m
HypertelorismYes(Yes)(Yes)YesNRNRNRNRNRNRNRNRNR
Prominent foreheadYesYesYesYesNRNRNRNRNRNRNRNRNR
Anteverted naresYesNRYesNRNRNRNRNRNRNRNRNRNR
Flat nasal bridgeYesYesYesNRNRNRNRNRNRNRNRNRNR
Micrognathia(Yes)NR(Yes)NRNRNRNRNRNRNRNRNRNR
MacrosomiaNRNRYesYesNRNRNRNRNRNRNRNRNR
PitsSacral dimple+dimples on sides of anklesEar pit (left)Ear pits, posterior helix (left)NRNRNRNRNRNRNRNRNRNR
Skin findingsDoughy hands
Fat pads on feet
Pronounced plantar creases
NRSoft skin
Doughy soft hands Furrowed forehead
Multiple nevi
NRNRNRNRNRNRNRNRNRNR
Skeletal abnormalitiesPectus excavatum
Kyphosis
NRScoliosis
Polydactyly
Narrow thorax
Increased intermammillary distance
Prominent sternum
NRNRNRNRNRNRNRNRNR
Increased CSF spaceYesYesYesYesNRNRNRNRNRNRNRNRNR
FontanelLarge anterior fontanelNRLate fontanel closureNRNRNRNRNRNRNRNRNRNR
HerniaInguinal and umbilicalInguinalInguinalNRNRNRNRNRNRNRNRNRNR
Brain imagingEnlarged lateral and third ventriclesMild volume lossMild volume loss
Thin corpus callosum
Cyst
Enlarged lateral ventricles
Hydrocephalus
NRNRNRNRNRNRNRNRNR
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
NDNDNDNDNDNDNDNDND
Small intestine, polypsNRNRNRNRYesNRHamartomatous juvenile intestinal polyps at 6 mNRNRYesYesYesNR
Additional cysts or tumoursNRNRNRNCMH 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 yNRPituitary blastoma at 8 mHodgkin lymphoma at 7 yPelvic sarcoma at 14 ySLCT bilat at 5 y and 13 y
Thyroid nodules at 7 y
NR
Other clinical findingsRespiratory distressPre-eclampsia in motherReduced 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 vesselsNRNRNRNRNRNR
  • 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.