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. 2018 Apr 26;26(7):996–1006. doi: 10.1038/s41431-018-0096-4

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.