BF:BFD[
6.2] → [
7.11979:12013]
BF:BFD[
7.12013] → [
7.4510:4510]
B:BD[
7.4510] → [
7.4511:4582]
∅:D[
2.248] → [
7.4668:11518]
B:BD[
7.4668] → [
7.4668:11518]
∅:D[
2.338] → [
7.11606:11750]
B:BD[
7.11606] → [
7.11606:11750]
∅:D[
2.1184] → [
7.11750:11751]
B:BD[
7.11750] → [
7.11750:11751]
∅:D[
2.3248] → [
7.11799:11978]
B:BD[
7.11799] → [
7.11799:11978]
B:BD[
7.11978] → [
2.3249:3478]
B:BD[
7.11751] → [
2.1185:3248]
B:BD[
7.11750] → [
2.339:1184]
B:BD[
7.11518] → [
2.249:338]
B:BD[
7.4582] → [
2.175:248]
# Idées
## OPHN1
Biblio :
- combien d'articles
- quelle dysmorphie ?
Carrier females are usually unaffected, probably due
to protective skewed inactivation of the X chromosome; nevertheless,
some paucisymptomatic females have been reported (most with a ran-
dom pattern of X inactivation), typically showing mild ID, minor cere-
bellar anomalies or strabismus (Boglis ̧ et al., 2020; Des Portes
et al., 2004; Iida et al., 2018; Moortgat et al., 2018; Schwartz
et al., 2019; Zanni et al., 2005).(
Patient 1: Facial dysmorphism was evident, including long face with prominent fore-
head, hypotelorism, deeply-set eyes, protruding ears, long nose, short
philtrum, thin upper lip and broad chi
frère) idem
cousine : (0 photos) same subtle dysmorphic features
patient autre famille : mild dysmorphic features, includ-
ing prominent ears, thin upper lip, full lower lip, and broad eyebrow
### @boglics20203 garçons
3 male : facial dysmorphism with a prominent forehead, long face, nystagmus, convergent strabismus, deep-set eyes, prognathism, and a prominent nose.
he facial features associated with OPHN1 syndrome reported by Ronzoni et al and Al-Owain et al comprise prominent supraorbital ridges, deep-set eyes, hypotelorism, thin upper lip, prognathism, and a short philtrum.[9,18] Only subject III-16, in our family report, presents the prognathism and deep-set eyes.
Strabismus represents a sign found in approximately 90% of previous reported OPHN1 mutations and is present in both investigated children.[3,8,9,15,16,18,20–23] Nystagmus has been described by Moortgart et al,Schwartz et al, and Zanni et al,[8,21,24] and it is also present in the proband (III-16). The facial dysmorphism seen in almost all affected patients could be explained by the expression of OPHN1 in the craniofacial bones.[24] Tall stature and macrocephaly have also been described in different families,[19] but not present in our investigated subjects (III-16, IV-2).
## Schwartz 2020 3 patients
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6310103/
Common Features of OPHN1 Reported in the Literature % (n) Our Study % (n)
Distinctive facies 84 (37/44) 100 (3/3)
Cerebellar hypoplasia 80 (35/44) 67 (2/3)
Ventriculomegaly 80 (36/45) 67 (2/3)
Strabismus 76 (29/38) 67 (2/3)
Genitourinary abnormalities 54 (14/26) 0 (0/3)
Behavioral Disorder 52 (17/33) 67 (2/3)
Seizures 43 (23/53) 100 (3/3)
Ataxia 40 (16/40) 100 (3/3)
Cf tableau pour dysmorpho des études
|Study Cohort|Patient 1|Patient 2|Patient 3|Moortgat 2018|Busa, 2017|Santos-Reboucas, 2014|Al-Owain, 2011|Madrigal, 2008|Zanni, 2005|Chabrol, 2005|des Portes, 2004|Philip, 2003|Bergmann, 2003
|Patient Profile||||A|B|C|D|||||A|B|C|D|||A|B|
|Age (years)|22|5|6|13,9,62,66|15,10|50,49,48,45,42, 27|7|7|8,4,33,18|19,17,15,2|NA|6|9, NA|NA,NA,4,27|8, NA|22,16 mo.|59,25,14,5|18,14,NA|13|21,20,13,5,2
|Variant|c.T590A |p.V197Ea|c.549dupT |p.Q184fsa|c.G2035A |p.D679Na|c.384+3A→C |p.V105_K128del|c.697C→T |p.Q233*|c.727C→T |p.R243W|c.1235G→A |p.G412D|Del Ex 3-15|Del Ex7|Del Ex7-15|Del 21+22|c.154+2T→C |p. ?|Del Ex 16+17|c.556C → T, p.Q186*|c.1645C→T, p.Q549*|c.644_645del |p.V215Gfs*35|Del Ex 19|c.745_752dup |p.K251Nfs*6|c.184C→T |p.Q62*|Del Ex19
|de novo|Yes|Yes|No|No|No|No|Yes|NA|No|No|No|No|No|No|No|No|No|No|Yes|No
|Macrocephaly|−|−|−|−,NA|−,−|−,−,−,−,−,−|−|−|−,−,−,−|NA|NA|NA|NA|+,+,NA,NA|−,−,−|NA|−,−,−,−|+,+,NA,+|+|−,−,−,−,−
|Prominent forehead|−|−|−|NA|NA|−,−,−,−,−,−|−|NA|+,+,−,−|+,+,+,+|NA|NA|NA|NA|NA|NA,+|NA|NA|NA|NA
|Long face|+|−|−|NA|+,−|−,−,−,−,−,−|−|NA|NA|+,+,+,+|+,+,+,+|NA|NA|+,+,NA,NA|+,+,+|+,NA|NA|+,+,+,+|NA|NA
|Short philtrum|+|−|−|NA|NA|−,−,−,−,−,−|−|NA|NA|NA|NA|NA|Mi.,+,+,+,+,+|+,+,NA,NA|+,+,+|NA|NA||+|NA
|Marked infraorbital creases|+|−|−|NA|NA|−,−,−,−,−,−|−|+|NA|NA|NA|NA|NA|NA|NA|+,+|NA|+,+,+,+|+|NA
|Prominent chin|−|−|−|NA,NA,+,+|+,−|−,−,−,−,−,−|+|NA|Mi.,+,+,Mi.|+,+,+,+|+,+,+,+|NA|Mi.,+,+,+,+,+|+,+,NA,NA|+,+,+|NA|NA|+,+,+,+|+|NA
|Large ears|+|−|−|NA|NA|−,−,−,−,−,−|−|NA|+,+,+,−|+,+,+,+|NA|NA|NA|NA|NA|+,+|NA|NA|NA|NA
|Hypotelorism|−|−|−|NA|NA|−,−,−,−,−,−|−|NA|−,−,−,−|NA|NA|NA|Mi.,+,+,+,+,+|+,+,NA,NA|+,+,+||NA|NA|NA|NA
|Deep-set eyes|−|−|+|+,+,−,−|−,−|−,−,−,−,−,−|−|NA|+,+,+,Mi.|+,NA,NA,NA|NA|NA|Mi.,+,+,+,+,+|+,+,NA,NA|+,+,+|+,NA|NA|+,+,NA,NA|+|NA
|Long, tubular nose/Prominent nasal root|−|−|+|NA|+,−|−,−,−,−,−,−|−|NA|+,+,+,+|+,+,+,+|+,+,+,+|NA|Mi.,+,+,+,+,+|+,+,NA,NA|+,+,+|NA|NA|NA|+|NA
|Thin upper lip|−|−|−|NA|NA|−,−,−,−,−,−|−|NA|NA|NA|NA|NA|Mi.,+,+,+,+,+|+,+,NA,NA|+,+,+|NA|NA|NA|NA|NA
|Strabismus|+|+|− (pseudo)|+,+,+,+|−,−|−,−,−,−,−,−|+|+|+,+,+,−|+,+,+,+|+,+,+,+|+|NA|NA|NA|+,+|+,+,+,+|NA|NA|+,+,+,+,+
|Nystagmus|+|−|−|+,+,NA|NA|−,−,−,−,−,−|−|−|NA|NA|NA|+|−,+,+,+,+,+|NA|+,+,+|NA|NA|−,−,−,−|−|NA
|Genitourinary
|Genitourinary abnormalities|−|−|−|NA,+,NA|NA|NA|NA|NA|−,−.+,−|NA|+,+,+,+|NA|NA|+,+,NA,NA|−,−,−|NA|−,−,+,−|NA|NA|+,+,+,+,+
|Neurologic
|Developmental delay|+|+|+|+,+,+,+|+,−|NA|+|+|+,+,+,−|+,NA,NA,+|NA|+|+,NA,NA,NA,NA,+|+,+,+,+|+,+,+|+,+|+,+,+,+|+,+,+,+|+|+,+,+,+,+
|Intellectual disability|+|n.e.|n.e.|+,+,+,+|+,−|+,+,+,+,+,+|+|−|S.,Mi.,S.,Borderline|Mo.,Mo.,Mo.,S.|+,+,+,+|+|+,Mo.,Mo.,Mo.,Mo.,S.|+,+,+,+|+,+,+|+,+|Mo.,Mo.,S.,S.|+,+,+,NA|+|+,+,+,+,+
|Speech delay|+|+|+|+,+,+,+|+,−|NA|+|+|+,+,Speech less,−|+, NA,NA,+|NA|+|+,NA,NA,NA,NA,+|+,+,+,NA|+,+,NA|+,+|+,+,+,+|+,+,+,NA|+|+,+,+,+,+
|Behavioral Disorder|+|+|−|+,+,+,+|+,+|NA|+|+|+,+,+,−|+,NA,NA,NA|NA|NA|NA|NA|+,NA,NA|NA|−,−,+,+|NA,NA,+,NA|+|NA
|Hypotonia|+|+|+|+,+,NA|−,−|−,−,−,−,−,−|−|−|+,Mi.,+,−|+,NA,NA,NA|NA|+|−,NA,NA, NA,NA,NA|NA|NA|NA,+|NA,+,+,+|+,+,+,−|NA|+,+,+,+,+
|Seizures|+|+|+|−,−,−,−|+,−|−,−,−,−,−,−|+|−|+,+,−,−|+,+,+,+|−,+,+,−|−|−,−,−,−,−,+|+,−,+,+|−,NA,NA|NA,+|+,−,+,+|−,−,−,−|−|+,+,+,+,+
|Seizure Onset|Infancy|4.5 years|2 years|NA|21 months|NA|6 years|NA|Infancy|8 years, NA,NA,Infancy|‘Early’|NA|NA|NA|NA|Infancy|NA,Infancy|NA|NA|Infancy
|Ataxic gait|+|+|+|+,+|+,+|NA|+|−|+,+,+,−|Mi.,Mi.,−,NA|−,−,−,−|+|−,−,−,−,−,−|NA|−,NA,NA|NA,−|−,−,−,−|−,−,−,−|−|+,+,+,+,+
|Spasticity|−|−|+|+,−,−,−|NA|NA|−|−|NA|NA|NA|NA|−,−,−,−,−,+|+,−,NA,NA|NA|NA|−,−,−,+|NA,NA,NA,+|−|NA
|Cerebellar hypoplasia|+|+|−|−,−,NA|−,−|NA,NA,NA,−,NA|−|−|+,+,+,+|+,+,Mi.,+|−,+,+,−|+|+,+,+,+,+,+|NA|+,+,+|+,+,+|NA,+,NA,+|+,+,+,+|+|+,+,+,+,+
|Ventriculomegaly|+|+|−|−,−,NA|+,+|NA,NA,NA,+,NA|−|+|+,+,−,+|+,+,−,+|−,+,+,−|+|+,+,+,+,+,+|NA,NA,NA,−|+,+,+|+,+,+|NA,−,NA,+|+,+,+,+|+|+,+,+,+,+
https://pubmed.ncbi.nlm.nih.gov/20528889/
prominent forehead, long flat facies, strabismus, large ears, long tubular nose, and prominent chin.
10.1093/brain/awg173
- des Portes 2004 : 4 hommes
10.1002/ajmg.a.20422
- Busa 2017 : 1 garçon
10.1097/MCD.0000000000000139
- chabrol 2005 : 7 garçons
10.1002/ajmg.a.30882
- zani 2005 : plusieurs garçons
10.1212/01.wnl.0000182813.94713.ee
- madrigal 2008 : garçons, pas de dysmorpho
- classen 2013 : 1 garçon
10.1007/s00439-013-1296-1
- zanni 2005 : garçpns
10.1212/01.wnl.0000182813.94713.ee
## Moortag 2018
Since 1998, OPHN1 mutations have been identified in 49 male and 14 female patie
Dysmorphic
features are often described in individuals with OPHN1 mutation, consisting of a long face
with deep-set eyes and marked infra-orbital creases, a long nose and a prominent chin [16, 18,
23]. However, these characteristics cannot be related to a specifically recognizable clinical
entity as it has been initially suggested, and absence of dysmorphism was previously reported
[1, 17, 20, 27, 30, 31]. In our cohort, the more severely affected patients (family A) presented
some of these reported facial features but affected individuals from family C, and family D
did not (Fig. 2).
Carrier females are usually described as asymptomatic, which could be attributed to protective skewed
inactivation of their affected X chromosome. This hypothesis is strengthened by the fact that a
random pattern of X chromosome inactivation is observed in most of the affected female
patients, usually with mild ID as in our cohort [23, 26, 28, 30], but occasionally with severe
symptoms [16] (Table 1). The large phenotypic variability in females might reflect that the
inactivation patterns measured in the peripheral blood may not be representative for other
tissues, in particular for the brain.
Moreover, it is now well-known that about 10% of X-
linked genes show variable patterns of inactivation and are expressed to different extents from
some inactive X chromosomes [33]. Interestingly, we noted that 1 out of 14 previously
reported female patients with a severe phenotype, including moderate to severe ID,
dysmorphic features and cerebellar signs, showed an extremely skewed X-inactivation pattern
[28]. We could hypothesize that this severely affected female expressed her X mutated allele.
However, expression studies to identify the inactive X chromosome were lacking in this
publication [28]
## Tentler 1999 2 soeurs, sans dysmorphie rapportée
https://www.nature.com/articles/5200320.pdf
## Autres
- Bergman 2003 : mère porteuse saine, strabisme seul
## Menten 2007 1 fille
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2688819/
Only a mild craniofacial dysmorphism with strabismus, a receding frontal hairline and mild hypotelorism was noted. On the trunk, a supernumerary nipple on both sides was present.
prominent maxillary incisors, relatively large ears and high forehead.
## Santos-Reboucas 2014 : famille avec 3 femmes
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3992576/
mère (atteinte++), grand-mère, tante (0 photos)
mère : machoire proéminente, Up standing palpebral fissures; relative large ears (5.9 cm; 50 percentile)
## Philip 2003
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1735502/pdf/v040p00441.pdf
Mère : macrocephaly (OFC 60 cm) and her facial appearance was very similar to that of her sons = slightly dysmor-
phic with deeply set eyes and a prominent chin.
## Al-Owain 2011 : 3 garçons avec légèe dysmorphie, *1 fille dysmorphique* (cf photo)
### @nuovo2021 : 3 hommes + 1 femme légèrement dysmorphique (0 photos)