Balkan Journal of Medical Genetics

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

CASE REPORT

Case 1. The second pregnancy of the couple was uneventful until the third trimester, when polyhidramnion, hypertelorsim and large gap between the toes were noticed. Quantitative fluorescence-polymerase chain reac-tion (QF-PCR) was performed at 36 weeks of gestation, and results were consistent with two copies of chromosomes 13, 18, 21 and male sex. Delivery was at term, birth weight was 2400g (below P5), length 50 cm (P50), head circumference 35 cm (P25-50), Apgar score 8/8. At birth, multiple dysmorphic features were noted: widely opened fontanel, hypertelorism, downslanting palpebral fissures, broad nasal bridge, low set ears, mandibular hypoplasia, pointy chin, cleft secondary palate, pectus carinatum, and broad toes. Hypotonia was also present, and he required ventilator support. Eye examination revealed microphtalmia of the left eye. Postnatal imaging examinations showed normal structure of abdominal organs and heart. No additional anomalies were present. The karyotype was normal, male. Four days after birth, the baby died due to development of severe respiratory distress. Postmortem autopsy confirmed clinical findings, skeletal radiographs showed notably shortened and broadened phalanges, with duplication of distal phalanges of the thumbs. Case 2. The subsequent (third) pregnancy of the couple was uneventful during the first trimester. Ultrasound examination at 22 weeks of gestation, showed normal fetal growth, however, broad nasal bridge, micrognathia and low set ears were detected (Figures 1 and 2). Fetal fingers were also broadly spaced with abducted thumb and possible agenesis of some metacarpal bones. Spina bifida in a lumbosacral region was also present (Figure 3). Fetal magnetic resonance imaging (MRI) was performed, confirming mandibular and nasal hypoplasia, as well as lumbosacral dysraphism with meningocele. Karyotyping yielded a normal male result. The pregnancy was terminated at 24 weeks of gestation at the parents request. Postmortem autopsy confirmed facial dysmorphism, hypertelorism, downslanting palpebral fissures and micrognathia. The index finger on both hands was significantly longer than the other fingers. The parents were referred for genetic counseling. After clinical examination, it was noted that the mother had mild facial dysmorphism: hypertelorism, downslanting palpebral fissures, broad nasal bridge, flat facial profile, prominent supraorbital ridges, pointy chin. She was otherwise healthy and of normal intelligence. In addition, we examined the daughter of the couple, and she showed similar facial dysmorphism as described in the mother. Neither mother nor daughter showed any additional skeletal changes. The pattern of anomalies in more severely affected male offspring and dysmorphic features present in the mother and daughter have led us to the tentative diagnosis of OPDSD. Clinical exome sequencing followed by Sanger sequencing of the fetal DNA isolated from cord blood (case 2) revealed a hemizygous missense pathogenic gene variant in the FLNA gene (NM_001110556.1: c.620C>T), converting the codon for amino acid 207 from proline to leucine (NP_001104026.1: p.Pro207Leu, rs28935469), thus confirming OPDSD in the proband. In concordance with this, mother and daughter were found to be heterozygous carriers of the same mutation.

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