Table 3.
A posteriori reevaluation of PTHS clinical signs in seven patients carrying a pathogenic mutation in TCF4
Patient MMPN166 | Patient APN149 | Patient B00H4MR | Patient MMPN68 | Patient APN214 | Patient APN210 | Patient B00H4R8 | Patient B00H4U1 | Patient (Redin et al., 2014) APN41 | Patient (Redin et al., 2014) APN117 | |
---|---|---|---|---|---|---|---|---|---|---|
TCF4 variant | c.873 C>A, p.(Tyr291*) | ac.990 G > A, p.? | c.1662del, p.(Asp554Glufs4*) | ac.1705C>T, p.(Arg569Trp) | c.1726C>T, p.(Arg576) | ac.1733G>A, p.(Arg578His) | ac.1841C>T p.(Ala614Val) | c.1927G>T p.(Glu643*) | ac.514_517del p.(Lys172Phefs*61) | ac.520 C>T, p.(Arg174*) |
Other variants/CNV | dup 22q11 | no | no | no | no | no | no | no | no | no |
Patient | Female | Male | Female | Male | Male | Female | Female | Female | Male | Female |
Age of inclusion | 4 y-o | 5 y-o | 4 y-o | 5 y-o | 18 y-o | 6 y-o | 7 y-o | 2 y-o | 3 y-o | 10 y-o |
Age of reexamination | 6 y-o | 9 y-o | 5y 8 m-o | 8 y-o | 20 y-o | 9 y-o | 7 y-o | 4 y-o | 6 y-o | 13 y-o |
Classical PTHS symptoms | ||||||||||
Facial gestalt | typical | mild | typical | mild | typical | mild | not typicalb | typical | mild | mild |
Growth (statural/ponderal) | M/M | M/M | −1/−2 | M/ + 5 SD | −3.5 SD/M | M/ + 3 SD | −3 SD/M | M/M | −2SD/−2SD | M/M |
Head circumference | −1 DS | M | −2.5 | M | M | +0,5 SD | +1.5 SD | M | M | −1.8 SD |
Cognitive impairment | profound | moderate | severe | profound | profound | moderate | severe | severe | severe | moderate |
Walking | absent | 16 mo | NA | 5 y | 3 y | 25 mo | 5 y | absent | 3 y | 28 mo |
Absent speech | yes | yes | no (few words) | yes | yes | yes | yes | yes | yes | no |
Hyperventilation/apneas | no | no | no | no | yes | yes | no | yes | no | no |
Happy appearance | yes | yes | no | no | yes | yes | NA | no | yes | yes |
Sleep disturbance | no | no | yes | no | yes | yes | no | no | no | yes |
Behavior problems | no | yes (Self-aggress.) | no | no | yes (Self-aggress.) | no | yes, severe | no? | yes (poor interactions) | no |
Stereotypic behavior | yes | no | yes | yes | yes | no | yes | yes | yes | no |
Seizures | yes (3–6 mo) | no | no | yes | yes | no | no | no | yes | no |
Hypotonia | yes | no | yes | yes | yes | no | no | yes | yes | yes |
Ataxic gait | no | no | yes | yes (mild) | yes | no | instable | no | yes | yes |
Ophthalmologic anomalies | yes strabismus | no | yes strabismus | yes | yes strabismus, astigmatism | yes Duane anomaly | No (ptosis) | yes strabismus hyperopia | no | no |
Constipation | no | yes | yes | yes | yes | yes | no | no | yes | yes |
Gastro-esophageal reflux | no | yes | no | no | yes | no | NA | yes (infancy) | yes | no |
Fetal pads | no | no | yes | yes | no | no | no | no | yes | yes |
Cerebral MRI | normal | – | abormal (1) | abnormal | abnormal | normal | abnormal (2) | normal | normal | normal |
Other signs | no | no | cervical syringomyelia | no | cryptorchidism, abolition of osteo-tendinous reflexes | headaches | no | heterotaxy, bifid uvula, long thumbs, labia minora hypoplasia | chronic otitis | no |
Whalen’s score (>12 or 15/20) | 16 | 7 | 15 | 15 | 17 | 13 | 13 | 15 | 12 | 9 |
Marangi’s score (>10/16) | 12 | 7 | 13 | 14 | 13 | 10 | 10 | 12 | 12 | 7 |
Conclusion PTHS | highly | no | highly | highly | highly | possibly | possibly | highly | possibly | no |
PTHS Pitt-Hopkins syndrome, y-o year-old; mo: months, SD standard deviation, M value in normal range, MRI Magnetic resonance imaging
a mutation previously described in databases or literature
b Rubinstein-Taybi facial features suggested. MRI anomalies 1: posterior atrophy of corpus callosum; 2: Hypersignal of the subcortical white matter in temporal lobes. The cDNA nomenclature given according to NM_001083962.1 isoform for all the variants.