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

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.



Number 26
Number 26 VOL. 26(2), 2023 All in one
Number 26
VOL. 26(2), 2023
Number 26
VOL. 26, 2023 Supplement
Number 26
VOL. 26(1), 2023
Number 25
VOL. 25(2), 2022
Number 25
VOL. 25 (1), 2022
Number 24
VOL. 24(2), 2021
Number 24
VOL. 24(1), 2021
Number 23
VOL. 23(2), 2020
Number 22
VOL. 22(2), 2019
Number 22
VOL. 22(1), 2019
Number 22
VOL. 22, 2019 Supplement
Number 21
VOL. 21(2), 2018
Number 21
VOL. 21 (1), 2018
Number 21
VOL. 21, 2018 Supplement
Number 20
VOL. 20 (2), 2017
Number 20
VOL. 20 (1), 2017
Number 19
VOL. 19 (2), 2016
Number 19
VOL. 19 (1), 2016
Number 18
VOL. 18 (2), 2015
Number 18
VOL. 18 (1), 2015
Number 17
VOL. 17 (2), 2014
Number 17
VOL. 17 (1), 2014
Number 16
VOL. 16 (2), 2013
Number 16
VOL. 16 (1), 2013
Number 15
VOL. 15 (2), 2012
Number 15
VOL. 15, 2012 Supplement
Number 15
Vol. 15 (1), 2012
Number 14
14 - Vol. 14 (2), 2011
Number 14
The 9th Balkan Congress of Medical Genetics
Number 14
14 - Vol. 14 (1), 2011
Number 13
Vol. 13 (2), 2010
Number 13
Vol.13 (1), 2010
Number 12
Vol.12 (2), 2009
Number 12
Vol.12 (1), 2009
Number 11
Vol.11 (2),2008
Number 11
Vol.11 (1),2008
Number 10
Vol.10 (2), 2007
Number 10
10 (1),2007
Number 9
1&2, 2006
Number 9
3&4, 2006
Number 8
1&2, 2005
Number 8
3&4, 2004
Number 7
1&2, 2004
Number 6
3&4, 2003
Number 6
1&2, 2003
Number 5
3&4, 2002
Number 5
1&2, 2002
Number 4
Vol.3 (4), 2000
Number 4
Vol.2 (4), 1999
Number 4
Vol.1 (4), 1998
Number 4
3&4, 2001
Number 4
1&2, 2001
Number 3
Vol.3 (3), 2000
Number 3
Vol.2 (3), 1999
Number 3
Vol.1 (3), 1998
Number 2
Vol.3(2), 2000
Number 2
Vol.1 (2), 1998
Number 2
Vol.2 (2), 1999
Number 1
Vol.3 (1), 2000
Number 1
Vol.2 (1), 1999
Number 1
Vol.1 (1), 1998

 

 


 About the journal ::: Editorial ::: Subscription ::: Information for authors ::: Contact
 Copyright © Balkan Journal of Medical Genetics 2006