OTOPALATODIGITAL SYNDROME TYPE I:
NOVEL CHARACTERISTICS AND PRENATAL
MANIFESTATIONS IN TWO SIBLINGS
Joksic I1,*, Cuturilo G2,3, Jurisic A1,2, Djuricic S4,5, Peterlin B6, Mijovic M2,
Karadzov Orlic N1,2, Egic A1,2, Milovanovic Z1,2
*Corresponding Author: Ivana Joksic, M.D., Ph.D., Gynecology and Obstetrics Clinic “Narodni Front”,
Kraljice Natalije 62, 11000 Belgrade, Serbia. Tel: +381-64-128-7643. Fax: +381-11-334-9651. E-mail:
ivanajoksic@yahoo.com
page: 83
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DISCUSSION
Mutations in the FLNA gene causative of OPDSD
are usually missense mutations or small deletions that do
not alter the reading frame, presenting a gain-of-functions
mutation [3,4]. Filamin A binds F-actin through the Nterminal
acting binding domain (ABD). The ABD is composed
of two calponin homology domains, CH1 and CH2,
which are highly conserved [3]. Mutations associated with
OPD type I cluster exclusively in the CH2 domain of the
protein, and it is considered that location of the mutation
predicts severity of the disease [4]. Mutations in the CH2
domain tend to alter its activity and disturb interaction with
F-actin, which is turn leads to cytoskeleton instability and
disruption of signal transduction [3]. Although it has been
shown that some mutations in CH2 (c.769G>A) increase
its affinity for F-actin, it is still not clear why chondrocyte
function is primarily affected, while function of other cell
types remains undisturbed [2,3].
The mutation found in our patients is located in CH2
amino acid position 207, leading to a substitution of proline
with leucine, and has previously been reported as pathogenic
and causative of OPD type I. So far, three families
with multiple affected males (total of seven individuals)
carrying the c.620C>T mutation have been described in
the literature [4-7]. Their clinical features are presented
in Table 1. All affected individuals had facial dysmorphy
(hypertelorism, downslating palpebral fissures), cleft palate,
broad thumbs and great toes, chest wall deformities
and deafness, features typical of OPD type I. Except for
the presence of unilateral microphtalmia and early neonatal
death in case 1, the phenotypes of patients from our study
is concordant with the clinical features described in other
carriers of this mutation, which further supports genotypephenotype
correlations in OPD type I. Although life expectancy
is described as normal, and perinatal and neonatal
mortality is not a feature of OPD type I, death of the boy
(case 1) implies that respiratory complications with fatal
outcome in early neonatal period can be expected even in
the mildest form of OPDSD [1,2]. As a further support of
possible respiratory complications in OPD type I, Robertson
et al. [7], described a case of a boy who had required
ventilator support until 4 months of age [7]. Ophtalomogic
findings are rare in OPD type I. Congenital glaucoma and
cataracts as well as corneal clouding have been described
in OPD type II and MNS, but so far, microphtalmia has
not been associated with any entity comprising OPDSD
[8]. Microphtalmia can be caused by different environmental
factors in early fetal development, such as infections,
radiation or vitamin deficiency [8]. As the TORCH (toxoplasmosis,
rubella, cytomegalovirus, herpes virus) analysis was negative in our patient and there were no indicators of
vitamin deficiency or radiation exposure, we estimate that
environmental factors are unlikely to be the cause of eye
anomalies in our case. Thus, we propose microphtalmia
as a possible new feature of OPDSD.
The phenotype of OPDSD seems to be poorly specific
in fetal development. To date, only nine fetuses with
an identified FLNA gene mutation have been reported,
but none are associated with the OPD type I phenotype
[9,10]. Ultrasonographic abnormalities detected in affected
fetuses can vary greatly and differential diagnosis of potential
disorders is very broad. All published prenatal cases
with verified FLNA gene mutations had a more severe
phenotype, OPD type II, MNS or FMD [9,10]. Even in
cases with multiple skeletal and extra skeletal anomalies
present, establishing a correct diagnosis is challenging
due to significant clinical overlap between these entities.
Filamin B related disorders, especially Larsen syndrome,
have several phenotypic similarities with OPD type I,
reflecting close homology with the FLNA gene [2]. Facial
dysmorphism, cleft palate, short digits and long bones are
common characteristic of OPD type I and Larsen syndrome,
but mode of inheritance as well as presence of
large joint dislocations differ in these two conditions. Oralfacial-
digital syndrome is another possible differential
diagnosis, considering the presence of telecantus, digital
anomalies and cleft palate in this syndrome [9]. Prenatal
diagnosis based on ultrasound examination is especially
challenging in OPD type I, given the fact that sometimes
only subtle skeletal malformations can be present. One of
the dysmorphic syndromes that usually presents with similar
but mild skeletal changes is Frank-ter Haar syndrome,
caused by mutations of the SH3PXD2B gene. However,
its autosomal recessive mode of inheritance could be distinguished
in some prenatal, familial cases [11]. In addition,
patohistological examination might be necessary in
order to make a more precise diagnosis as well as detailed
examination of the parents and family members, who can
also present with subtle signs of OPDSD. Next generation
sequencing techniques are very valuable diagnostic tools
in case of diagnosing a condition with a broad differential
diagnosis such as OPDSD.
In conclusion, we suggest that the presence of hypertelorism,
micrognathia, digital anomalies (wide spaced
toes and broad thumbs) on prenatal ultrasound examination
should alert suspicion to OPDSD. Detailed clinical
examination of mother and other female relatives is of
great importance in establishing definitive diagnosis of
OPDSD. Microphtalmia and early neonatal death due to
respiratory complications are suggested as a novel clinical
features in OPD type I.
Declaration of Interest. The authors report no conflicts
of interest. The authors alone are responsible for the
content and writing of this article.
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