Table 1

Clinical and molecular features of the 17 patients with an TFE3 mutation

Patient 1Patient 2Patient 3Patient 4Patient 5Patient 6
Age20 years20 years3 years and 2 months18 months10 years29 months
PregnancyHigh serum markers, normal foetal karyotypeUncomplicatedOligohydramnios, third trimester IUGRUncomplicatedUncomplicatedUncomplicated
Term (WG), birth weight/length/OFC (SD)36, –1/+0.5/NA−141, –2/NA/NA41, +2/>+3/+238, +1/–1/−1Term, 0/+0.5/+0.5
Neonatal featuresHypoglycaemiaPlagiocephalyJaundice, transient neonatal hepatomegalyFeeding difficulties
DD/IDSevereSevereSevereSevere (no interaction, low head control)SevereSevere (head control)
Age of walkingNot acquired40 monthsNot acquiredNot acquiredNot acquiredNot acquired
SpeechNo speechFew wordsNo speechNo speechNo speechNo speech
Epilepsy (age of onset)+7 months+10 years+17 months+6 years
Developmental regression (age)PM regression (7 m.)PM regression (9 m.)Regression (infancy)
Neurological phenotypeHypotoniaHypotoniaSevere truncal muscular hypotonia, distal hypertoniaHypotonia, lower limb spasticity
Behavioural issuesAutistic behaviour (stereotypic movements)NASleep disturbance
Brain MRINormalNormalNormalNormalShort corpus callosumHydrocephaly (acqueducal stenosis)
Facial phenotypeHigh forehead
 Widely spaced eyes+++++
 Anteverted nares/short noseBifid nose+/++/++/NA+/++/+
 Flat nasal bridge++++++
 Coarseness++ protruding tongue++++
 Thick lips++++-
 Pink and full cheeks++++++
 Almond-shaped eyes++++++
 Thick earlobes+++NA++
Length (SD)−4.5−4−1.4+1.4−4−1
BMI (centile)25 (80th)30 (92th)17.5 (90th)19.9 (95th)1918 (90th)
OFC (SD)NA0−1+0.700
Orthopaedic anomalies
 Flat feet++
 Hip dislocation+Unilateral dysplasia
 Genu valgum+
 Club feet+
Skeletal X-raysNDNormalNDNDMetaphyseal enlargementShort metacarpals and long bones
Abnormality of skin pigmentationBlaschko’s linesBlaschko’s linesBlaschko’s linesBlaschko’s lines
Umbilical hernia+
Eye findingsStrabismusStrabismus, impaired visionHyperopiaAbnomality of the VEPStrabismus, depigmented iridian macule
Hearing lossUnconclusive hearing test++
OtherAortic insufficiency, body asymmetryClubbing of fingersLateral semicircular canal dysplasia, laryngomalacia
Recurrent infectionsChronic upper airways infectionsNA+
Metabolic workupNDNormalNormal alpha-L-iduronidase activityAlanine-lysine ratio in plasma<3, elevated lactate in bloodMuscle biopsy: fat accumulation, irregular fibre sizeNormal
Chromosome X inactivationBlood: skewed (89%)
Fibroblasts: random
Fibroblasts: skewedBlood: skewed (>97%)
Fibroblasts: random
TFE3 variantc.356A>C p.Gln119Proc.557C>T p.Pro186Leuc.560C>T p.Thr187Metc.559A>C p.Thr187Alac.572T>C p.Leu191Proc.572T>C p.Leu191Pro
Patient 7Patient 8Patient 9Patient 10Patient 11Patient 12
Age4 years and 3 months14 years10 years22 years9 years12 months
PregnancyUreteral dilatation, gestational diabetesUncomplicatedUncomplicatedTegretolUncomplicatedNA
Term (WG), birth weight/length/OFC (SD)38, +2/0/039, 0/0/NA39, +1/NA/NA36+6, 0/NA/NA36+6, –0.5/−1/–1.839, –1/−1/–1
Neonatal featuresNeonatal hypotonia, feeding difficultiesNeonatal jaundiceFeeding difficulties
DD/IDSevere (sat at 12 months)SevereSevereSevereSevereSignificant DD
Age of walkingNot acquired6 years30 months7 years (walks with assistance)Not acquiredNot acquired
SpeechNo speechNo speech3 years (single words)No speechNo speechNo speech
Epilepsy (age of onset)+4 years+10 years+10 yearsOne seizure (5 years)
Developmental regression (age)Loss of words (infancy)Loss of babbling (9 m.)
Neurological phenotypeHypotonia-Increased reflexes, tremor of the upper extremities, wide-based gaitHypotonia, mild spasticity (left side)Hypotonia
Behavioural issuesHand stereotypies, sleep disturbance, autismHappy behaviour, sleep disturbanceAutistic behaviour (stereotypies)Autistic behaviour (stereotypies)
Brain MRINormalNormalNormalAbnormal myelinationNormalND
Facial phenotypeBroad forehead
 Widely spaced eyes+++
 Flat nasal bridge+++++NA
 Anteverted nares/short nose+/++/++/NA+/+++
 Coarseness+++, protruding tongue+
 Thick lips+++++
 Pink and full cheeks++++
 Almond-shaped eyes++++
 Thick earlobes++++++
Length (SD)+2.5−3−2.8−3.5−2.5+1
BMI15.4 (50th)22.4 (85th)25 (90th)2117.595th
OFC (SD)+1−0.5+0.5NANA+0.5
Orthopaedic anomalies
 Flat feet+++
 Hip dislocation
 Genu valgum+
 Club feet++Left
Skeletal X-raysNormalNormalNDNDNDND
Abnormality of skin pigmentationBlaschko’s linesBlaschko’s linesBlaschko’s linesLarge hyperpigmented region on the abdomenBlaschko’s lines+
Umbilical hernia
Eye findingsHyperopia
Hearing loss+Conductive
Recurrent infections
OtherHistiocytofibroma (4 years)Patent ductus arteriosus, gastro-oesophageal refluxChronic constipationBody asymmetry
Metabolic workupNDHypercholesterolaemia. Normal lysosomal activities in leucocytesMPS, OGS, UAA, OA screening: normalNormal, skin biopsy negative for GM1, Niemann-Pick, and Gaucher diseasesNDND
X inactivationBlood : skewed (91%)NDNDNDND
TFE3 variant (NM_006521.4)c.602A>C p.Gln201Proc.560C>A; p.Thr187Lysc.780+1G>Ac.551A>G p.Glu184Glyc.560C>T p.Thr187Metc.570C>G p.His190Gln
Patient 13Patient 14Patient 15Patient 16Patient 17
Age22 years4 years 5 months6 years 6 months7 years5 years
PregnancyGestational diabetesUncomplicatedNANAUncomplicated
Term (WG), birth weight/length/OFC (SD)41, –0.5/−1/–1NA, −1/NA/NANA33, NA/NA/NATerm, −1/NA/+1
Neonatal featuresHepatomegaly (4 months)JaundiceCholestasis, hepatomegaly, hypoglycaemia
DD/IDSevereSevereSevereSevere (sat 4 years)Severe
Age of walkingNot acquired30 m3yNot acquiredNot acquired
SpeechNo speechNo speechNANo speechNo speech
Epilepsy (age of onset)+ (<1 year)+ (NA)+ (day 1)
Developmental regression (age)
Neurological phenotypeSpastic tetraplegia, ataxic gaitHypotoniaHypotonia, spasticityHypotonia
Behavioural issuesAutistic behaviour (stereotypies, self-injuries) Sleep disturbanceAutistic behaviourAutismAutistic behaviour, sleep disturbanceSleep disturbance
Brain MRIUnspecific changes in paraventricular myelination, generalised cerebral atrophy, retrocerebellar arachnoid cystNormalNormalArachnoid cyst, Dandy-Walker malformationHydrocephaly, periventricular white matter lesions
Facial phenotypeFlat faceProminent forehead
 Widely spaced eyes++++
 Anteverted nares/short nose++/NA–/NA+/++/+
 Flat nasal bridge+++++
 Thick lips+++
 Pink and full cheeks+ (full cheeks)++++
 Almond-shaped eyes++++
 Thick earlobes++++
Length (SD)−4+2−1−2.63−4.5
BMI (centile)231621.3 (>95th)20 (>95th)16.6 (80th)
OFC (SD)−10+1+1.9−0.4
Orthopaedic anomalies
 Flat feet++
 Hip dislocationHip dysplasia+
 Genu valgum+NA
 Club feet+
Skeletal X-raysAdvanced bone ageNDNDNDNormal (thorax)
Abnormality of skin pigmentationBlaschko’s linesBlaschko’s lines
Umbilical hernia+NA+
Eye findingsStrabismus, severe myopia, retinal degenerationOculomotor apraxiaStrabismusCortical visual impairment, strabismus, amblyopia
Hearing loss++
OtherClubbing of fingers, splenomegaly, anteriorly displaced anus, kidney asymmetryInterstitial lung disease, chronic diarrhoeaPosterior plagiocephalyChronic lung disease (4 m.), sleep apnoea syndromeBronchomalacia, cardiac left ventricle dilatation, hypospadias, clubbing of fingers
Recurrent infectionsRecurrent lung infections+ (neutropenia)+
Metabolic workupNDNormalNDNDNormal metabolic screening, fat and glycogen accumulation, decreased muscular ATP production and substrate oxidation
TFE3 variantc.566A>G, p.(Tyr189Cys)c.350G>A p.Arg117Glnc.350G>A: p.Arg117Gln Mosaic (88%)c.560C>T p.Thr187Metc.560C>G p.Thr187Arg Mosaic (65%)
  • BMI, body mass index; DD, developmental delay; ID, intellectual disability; IUGR, intrauterine growth retardation; m., months; NA, not applicable; ND, not done; OFC, occipitofrontal circumference; PM, Psychomotor; TFE3, transcription factor 3; VEP, visual evoked potential; WG, weeks of gestation.