First Report of Jacobsen Syndrome with Dextrocardia Diagnosed with del(11)(q24q25)

• Jacobsen Syndrome is characterized by a deletion of chromosome 11, and there are several cases reported in the literature with classical findings.

• This is the first case with dextrocardia diagnosed as Jacobsen syndrome and not showing thrombocytopenia or bleeding disorder.

• Up to date, there is no report of Jacobsen syndrome with dextrocardia diagnosed with del(11)(q24q25).

Jacobsen syndrome (OMIM #147791) is a contiguous gene syndrome that is based on the terminal deletion of the long arm of chromosome 11 [Mattina et al., 2009]. The syndrome was first defined by Jacobsen et al. [1973]. The main clinical findings in the 11q deletion syndrome are thrombocytopenia, Paris-Trousseau syndrome, developmental delay, congenital heart disease, short stature, abnormal brain imaging, and pyloric stenosis [Grossfeld et al., 2004].

In this report, we present a case examined in our clinic with coarse facial appearance and dextrocardia and diagnosed as Jacobsen syndrome with 11q deletion.

A 10-year-old female was referred to our clinic with congenital heart disease, dextrocardia, and coarse facial appearance (Fig. 1). When she was 3 days old, computed tomography showed dextrocardia (Fig. 2). She had a history of growth retardation and a cardiac operation for ventricular septal defect when she was 5 months old. Abdominal ultrasonography showed that liver, spleen, and stomach had no pathologies, and they were located in correct anatomical positions. The patient had a platelet count of 312,000; she had no bleeding problem up to the age of 10 years.

Our patient was born by cesarean section at term with a weight of 3,500 g (50th–75th centile). At the neonatal period she had physiological jaundice. Developmental milestones were normal, she started walking and talking at the age of 1 year. Brain MRI results taken at the age of 3 years were normal. A mucopolysaccharidosis test was performed at another center before, and the result was normal. On her physical examination at 10 years, height was 132 cm (10th–25th centile), and weight was 27 kg (10th–25th centile). When the clinical features of the patient were evaluated, chromosome analysis and array-CGH analysis were planned.

Chromosome analysis was performed on cells from a heparinized peripheral blood sample taken from our patient after phytohemagglutinin-stimulated short-term lymphocyte culture, using the Giemsa trypsin banding method. A total of 50 metaphases were evaluated, and a deletion in the long arm (q24q25) of chromosome 11 was detected: 46,XX,del(11)(q24q25) (Fig. 3).

Genomic DNA was isolated from the peripheral blood using the EZ1 DNA Blood Kit. Array-CGH was performed using 4 × 180K CGH+SNP oligoarray (Agilent Technologies, Palo Alto, CA, USA). A 9-Mb deletion of 11q24.2q25 was detected: arr[hg19] 11q24.2q25(125,852,593_134,934,196)×1 (Fig. 4; Table 1). The left part of Figure 4 shows the deletion, indicated by the large purple arrow. The outputs of the study were analyzed with Agilent Cytogenomics v4.0.3 program. Losses (deletion) covering chromosome region 11q24.2q25 were associated with Jacobsen syndrome. Segregation analysis showed that the deletion was de novo.

Jacobsen syndrome is a clinical disorder caused by segmental aneusomy and monosomy due to the deletion of the 11q23 terminal region [Fryns et al., 1986; Penny et al., 1995]. The deletion in 11q varies between 7 and 20 Mb, and deletions under 2.9 Mb were associated with this syndrome. It has been reported that 75% of the cases are women [So et al., 2014]. There are different phenotypic correlations with the size of the deletion. Deletion of genes has been suggested to have a cumulative effect on the prognosis of the disease [Mattina et al., 2009]. The deletion size and phenotypic features of our patient were compared with previously reported cases and are shown in Table 2.

A case was reported with the del(11)(q24.2qter) of 8.9–9.8 Mb and ventricular septal defect [Giampietro et al., 2006]. On the other hand, del(11)(q24.2q24.3) of 2.4 Mb was detected with thickened mitral valve flaps and an accessory thin tendon structure on the septum [Tassano et al., 2016]. In our case, the 9-Mb deletion was associated with congenital heart disease, dextrocardia, and coarse facial appearance. In the cases of Bernaciak et al. [2008] and So et al. [2014], 5-Mb and 3.162-Mb deletions, respectively, were reported. ETS1 is located in the deletion region. The ETS1 gene is expressed in the endocardium and is responsible for normal development of the heart. It has been reported in previous studies that deletion of the gene causes ventricular septal defect [Ye et al., 2010]. Giampietro et al. [2006] suggested that the deletion of the TECTA gene may cause hearing loss in the left ear in their study. Although in our patient the deleted region includes the TECTA gene, hearing loss was not detected; however, growth retardation and mild intellectual disability were observed compared to her peers.

One of the important clinical features of Jacobsen syndrome is thrombocytopenia, which is similar to Paris-Trousseau syndrome. Deletion in the FLI1 gene may cause thrombocytopenia [Favier et al., 2003; Fujita et al., 2010]. Although the FLI1 gene is included in the deletion region of 9 Mb in our case, thrombocytopenia was not detected in our patient.

In our patient, the deletion covers a large region. Phenotypic features may be caused by a single gene or the cumulative effect of a combination of contiguous genes to possible gene-gene interactions. The deletion size of patients helps us to understand phenotype-genotype correlations [Krishnamurti et al., 2001; Fujita et al., 2010]. Mosaic trisomy 11 has been reported earlier by Wilmot et al. [1983] and Balasubramanian et al. [2010]. Our case showed no mosaic trisomy 11. So our case differs from the other Jacobsen syndrome cases reported before by the presence of dextrocardia and absence of thrombocytopenia.

Written informed consent was obtained from the parents for publication of this case report and any accompanying images. The paper is exempt from ethical committee approval. Ethical approval was not required for this study in accordance with local/national guidelines.

The authors have no conflicts of interest to declare.

No funding was received for this study.

Concept and design: S.Y., D.Z., H.S.G. Resources: S.Y., D.Z., H.S.G. Materials: S.Y., D.Z., H.S.G., E.I.A., C.M. Data collection and/or processing: S.Y., D.Z., H.S.G., E.A., S.D., H.G. Analysis and interpretation: D.Z., H.S.G., E.A., S.D., E.I.A., C.M. Literature review: S.Y., D.Z., H.S.G. Writing manuscript: S.Y., D.Z., H.S.G., E.A., H.G. Critical review: S.Y., E.A., H.G.

All data generated or analyzed during this study are included in this article. Further inquiries can be directed to the corresponding author.