Table 1 Clinical findings
Patient | P1/FI a | P2/FII a | P3/FIII a | P4/FIII | P5/FIV | P6/FIV | P7/FV a | P8/FVI a | P9/FVII a |
|---|---|---|---|---|---|---|---|---|---|
Age/gender | 9 y/F | 9 y/F | 13 y/M | 6 y/M | 8 y/M | 4 y/M | 11 y/F | 9 y/F | 3 y/F |
Origin | Egypt/Arab | Iran | Pakistan | Pakistan | Pakistan | Pakistan | Croatia | Austria | Brazil /Caucasian |
FKBP14 mutations | c.523dupG p.(Val175Glyfs*3) homozygous | c.143 T > A p.(Met48Lys) homozygous | c.197 + 5_197 + 8del p.(His67*) homozygous | c.197 + 5_197 + 8del p.(His67*) homozygous | c.197 + 5_197 + 8del p.(His67*) homozygous | c.197 + 5_197 + 8del p.(His67*) homozygous | c.362dupC p.(Glu122Argfs*7) homozygous | c.362dupC p.(Glu122Argfs*7) homozygous | c.362dupC p.(Glu122Argfs*7) homozygous |
Skin | |||||||||
Hyperextensible | – | + | (+) | + | – | – | + | (+) | – |
Soft texture | (+) | + | + | + | + | + | + | + | + |
Criss cross palms/soles | – | – | – | + | + | + | – | – | – |
Follicular hyperkeratosis | – | – | – | – | – | – | (+) | (+) | – |
Easy bruising | – | + | – | – | – | – | (+) | – | – |
Hypertrophic scars | (+) | – | – | – | – | – | – | – | – |
Atrophic scars | – | – | (+) | – | – | – | – | – | – |
Other skin anomalies | – | – | – | Thin skin, redundant skin | Hypertrichosis | Hypertrichosis | – | Hypertrophy at pressure points | – |
Joints and skeleton | |||||||||
Hypermobile large joints | + | – | + | + | + | + | + | + | + |
Hypermobile small joints | + | + | + | + | + | + | + | + | + |
Beighton score | 9/9 | NR | 9/9 | 9/9 | 8/9 | NR | 9/9 | 6/9 | 9/9 |
Congenital hip dislocation | + | – | – | – | + | – | – | – | + |
Recurrent dislocations | +(Hips) | – | – | – | – | – | – | – | – |
Joint contractures | – | – | – | – | +(Fingers, elbows, knees) | +(Fingers) | – | +(Elbows) | – |
Progressive kyphoscoliosis | +(Onset 6 m) | Scoliosis (5 m) | +(Onset 3 m) | +(Onset birth) | +(Onset 2.5 y) | +(Onset 6 m) | +(Onset 1 y) | +(Onset 3 m) | +(Onset 7 m) |
Foot deformities | Congenital vertical talus | Cong. talipes, pes planus | Pes planovalgus | Pes planovalgus | Postural talipes | Postural talipes | Postural talipes, pes valgus | Pes planovalgus | Postural talipes, pes planovalgus |
Other skeletal anomalies | Knee instability | – | – | – | Pectus carinatum, radioulnar synost. | – | – | – | – |
Fractures | – | – | – | – | – | – | – | – | – |
Neuromuscular | |||||||||
Muscle hypotonia at birth | + | + | + | + | + | + | + | + | + |
Poor head control in infancy | + | + | + | + | + | + | + | + | + |
Weakness improving | + | NR | + | + | + | + | + | + | + |
Delayed motor development | + | + | + | + | + | + | + | + | + |
Walking independently | 3.5 y | 7 y | 4 y | 4.5 y | 3 y | Only supported | 2.5 y | 3.5 y | 2 y |
Muscular atrophy | – | – | +(Shoulder) | NR | + | + | + | + | – |
Cardiovascular | |||||||||
Cardiac valve abnormalities | – | – | – | NR | – | + | – | – | – |
Septum defects | – | Small ASD | – | NR | Small ASD | – | – | – | – |
Vascular abnormalities | – | – | NR | NR | Borderline aortic root diameter | NR | – | – | Mild aortic ectasia at 3.5 y |
Eyes and ears | |||||||||
Bluish sclerae | – | – | + | + | + | – | – | (+) | (+) |
Refraction anomaly | Myopia | Myopia | Hyperopia | Hyperopia | NR | NR | Myopia | – | – |
Other eye anomalies | Nystagmus in infancy, squint | – | Squint | – | Retinopathy of prematurity | Squint | – | Squint | – |
Hearing impairment | – | – | Conductive, moderate | Conductive, borderline | Sensorineural, profound, CI | Conductive, moderate | Sensorineural, mild | Sensorineural, moderate | – |
Miscellaneous | |||||||||
Pregnancy and birth | PROM, 33/40 | IUGR, Polyhydr., PROM, 31/40 | Polyhydramnios | IUGR | AIS | ||||
Reduced fetal movements | + | – | – | – | – | – | + | + | + |
Feeding difficulties | + | – | +(PEG) | +(PEG) | +(PEG) | – | – | – | – |
Cleft palate, bifid uvula | – | – | + | + | + | – | – | – | – |
Micrognathia, retrognathia | – | – | – | + | + | + | + | – | – |
Other craniofacial and upper gastrointestinal anomalies | Delayed closure of fontanel | – | – | – | GER, fundoplication | GER, fundoplication | High arched palate, GER | Overbite in infancy | – |
Respiratory tract anomalies | – | – | – | Laryngomalacia | Ventilation for 6 m, tracheostomy | Tracheomalacia, Noct. ventilation | – | – | – |
Herniae | Umbilical | – | – | – | Umbilical, inguinal | – | Umbilical | – | Inguinal |
Genitourinary system anomalies | – | – | – | – | Bilateral UDT, hydronephrosis | – | – | – | – |
Speech or language delay | – | Dysarthria | + | + | + | + | – | + | – |
Learning difficulties or ID | – | – | Mild ID, functioning at 9 y | Mild ID, functioning at 4 y | – | – | – | – | – |
Brain MRI | ND | Dilated ventricles | ND | ND | ND | ND | Normal (2.5 y) | Mildly dilated ventricles (9 m) | ND |
Patient | P10/FVIII a | P11/FIX | P12/FX a | P13/FXI a | P14/FXII | P15/FXIII a | P16/FXIV | P17/FXV |
|---|---|---|---|---|---|---|---|---|
Age/gender | 15 y/F | 6 y/M | 9 y/F | 5 y/F | 16 y/M | 36 y/F | 24 y/M | 11 m/M |
Origin | USA/Caucasian | USA/Caucasian | Poland | GB/Caucasian | Turkey | GB/Caucasian | GB/Caucasian | GB/Caucasian |
FKBP14 mutations | c.362dupC p.(Glu122Argfs*7) homozygous | c.362dupC p.(Glu122Argfs*7) homozygous | c.362dupC p.(Glu122Argfs*7) homozygous | c.362dupC p.(Glu122Argfs*7) homozygous | c.362dupC p.(Glu122Argfs*7) homozygous | c.362dupC p.(Glu122Argfs*7) homozygous | c.362dupC p.(Glu122Argfs*7) homozygous | c.362dupC p.(Glu122Argfs*7) homozygous |
Skin | ||||||||
Hyperextensible | + | + | (+) | – | + | (+) | (+) | + |
Soft texture | + | + | + | + | + | (+) | NR | + |
Criss cross palms/soles | + | – | – | + | – | – | – | – |
Follicular hyperkeratosis | – | (+) | + | + | – | NR | + | – |
Easy bruising | + | + | + | – | + | – | + | – |
Hypertrophic scars | + | – | – | – | – | – | + | – |
Atrophic scars | + | – | – | – | – | – | – | – |
Other skin anomalies | Translucent skin | Adhesives peel off the skin | – | Cutis marmorata | – | – | – | – |
Joints and skeleton | ||||||||
Hypermobile large joints | – | + | + | + | + | + | + | + |
Hypermobile small joints | + | + | + | + | + | + | + | + |
Beighton score | NR | NR | 6/9 | 8/9 | NR | 6/9 | 5/8 | 6/9 |
Congenital hip dislocation | – | – | + | – | – | – | – | – |
Recurrent dislocations | – | – | +(Patella) | – | + | – | +(Knees) | – |
Joint contractures | +(Elbows) | +(Fingers) | – | +(Wrists) | – | – | – | +(Fingers) |
Progressive kyphoscoliosis | +(Onset 1.5 y) | +(Onset 7 m) | +(Onset 7 y) | +(Onset 1.5 y) | – | +(Onset 6–12 m) | +(Onset infancy) | Mild scoliosis |
Foot deformities | Pes valgus | Congenital talipes | Pes planus | Cong. talipes, pes valgus | Pes planovalgus | Pes planus | Congenital talipes | Postural bilat. talipes equinovarus |
Other skeletal anomalies | Loose patellae | Pectus carinatum, later excavatum | Pectus excavatum | Pectus excavatum | Vertebral fusion of C1 and C2 | – | – | – |
Fractures | (+) | – | – | – | + | – | – | – |
Neuromuscular | ||||||||
Muscle hypotonia at birth | + | + | + | + | + | + | + | + |
Poor head control in infancy | + | + | + | + | + | + | + | + |
Weakness improving | + | + | + | + | + | + | + | + |
Delayed motor development | + | + | + | + | + | + | + | + |
Walking independently | 3 y | 3 y | 2 y | 3 y | 7 y | 3.5 y | 3.5 y | – |
Muscular atrophy | +(Neck, UE, LE) | – | + | – | + | – | – | – |
Cardiovascular | ||||||||
Cardiac valve abnormalities | – | + | + | – | + | – | + | + |
Septum defects | – | – | PFO | – | – | – | – | Small ASD, small muscular VSD |
Vascular abnormalities | – | – | – | – | – | – | Possible coronary artery dissection | Dilated aorta |
Eyes and ears | ||||||||
Bluish sclerae | – | – | – | – | + | – | – | (+) |
Refraction anomaly | – | – | Myopia | Astigmatism | NR | Myopia | Hyperopia | – |
Other eye anomalies | Squint | – | – | – | – | – | – | – |
Hearing impairment | Sensorineural, mild | – | Sensorineural, moderate | – | Severe, bilateral hearing aids | Sensorineural, moderate | – | Moderate high frequency loss (left ear) due to middle ear effusion |
Miscellaneous | ||||||||
Pregnancy and birth | IUGR, oligohydr., PROM, 35/40 | 35/40, neonatal sepsis | 36/40, TRD | |||||
Reduced fetal movements | + | + | – | – | – | – | – | – |
Feeding difficulties | + | – | – | + | + | (+) Slow to feed | – | – |
Cleft palate, bifid uvula | – | – | – | – | + | – | – | + |
Micrognathia, retrognathia | – | – | + | – | – | – | – | + |
Other craniofacial and upper gastrointestinal anomalies | – | – | Delayed closure of fontanels, GER | – | Malocclusion, crowded teeth | – | GER | – |
Respiratory tract anomalies | – | – | – | – | – | – | – | – |
Herniae | – | – | Diastasis recti | Umbilical | Umbilical | – | – | – |
Genitourinary system anomalies | NR | – | – | – | Bladder diverticulae | NR | – | – |
Speech or language delay | – | – | – | + | + | – | – | – |
Learning difficulties or ID | – | – | – | – | Mild learning difficulties | – | – | – |
Brain MRI | Normal (infancy) | ND | Normal (9 m) | ND | WM volume decreased (9 y) | ND | ND | ND |
