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Interstitial 5p15.2-p13.3 deletion in association with situs inversus, dextrocardia, L-loop of the ventricles, and transposition of great arteries in a newborn infant

Part of: Basic Science

Published online by Cambridge University Press:  23 July 2019

Shabih Manzar Open the ORCID record for Shabih Manzar [Opens in a new window] ,
Nitin Walyat  and
Ryan C. Jones
Shabih Manzar*
Affiliation:
Department of Pediatrics, College of Medicine, Louisiana State University of Health Sciences, Shreveport, LA, USA
Nitin Walyat
Affiliation:
Department of Pediatrics, College of Medicine, Louisiana State University of Health Sciences, Shreveport, LA, USA
Ryan C. Jones
Affiliation:
Department of Pediatrics, College of Medicine, Louisiana State University of Health Sciences, Shreveport, LA, USA
*
Author for correspondence: S. Manzar, Department of Pediatrics, College of Medicine, Louisiana State University of Health Sciences, 1501 Kings Highway, Shreveport, LA 71130, USA. Tel: +1 318-626-4374; Fax: +1 318-698-4305; E-mail: smanza@lsuhsc.edu
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Abstract

We report a rare association of interstitial deletion of 5p15.2-p13.3 with situs inversus, dextrocardia, L-loop of the ventricles, and transposition of great arteries: [I, L, L] Transposition of Great Arteries. We did not find such an association reported in the medical literature.

Keywords

Deletionnewborndextrocardiatransposition of great arteries

Information

Type
Brief Report
Information
Cardiology in the Young , Volume 29 , Issue 8 , August 2019 , pp. 1115 - 1117
Copyright
© Cambridge University Press 2019 

Case

A female infant is born at 35 3/7 weeks of pregnancy to a 36-year-old G4P0131 mother. The duration of rupture of membrane was 6 hours. All maternal prenatal laboratory results including rapid plasma reagin, human immunodeficiency virus, hepatitis B, chlamydia and gonorrhea were negative. Maternal past medical history was positive for Human simplex virus (last outbreak 1 year ago), systemic lupus erythematosus, deep vein thrombosis, and seizure disorder for which she was treated with levetiracetam.

At delivery, the infant required resuscitation with positive pressure ventilation. Apgar scores were 2, 7, and 9 at 1, 5, and 10 minutes, respectively. Cord gas showed a pH of 7.31, PCO2 of 41, PO2 of 55, and HCO3 of 19.7. Infant’s measurements were appropriate for gestational age, with weight 2.13 kg (4 lb 11.1 oz), length 47 cm (1′ 6.5″), and head circumference 29.5 cm (11.61″). Admission vital signs were stable: temperature, 99.1°F (37.3°C); heart rate, 196; respiration, 32; blood pressure, 67/35 mmHg with a mean of 44; SpO2, 93%.

Physical examination showed flat anterior fontanelle. No facial dysmorphic features were noted with normal appearing cranium and face. No hypertelorism was noted with normal nose. Back and neck were normal. Cardiovascular exam showed regular rhythm, S1 normal and S2 normal, and no murmur heard. Pulses were palpable in all limbs. Point of maximum impulse was displaced to the right chest. Chest exam showed retraction and tachypnea. Abdomen was soft with no distension or hernia. Musculoskeletal exam showed talipes equinovarus. Ortolani and Barlow test was negative. Genital exam showed normal female. She was noted to be lethargic with low muscle tone. Skin was warm and dry. Capillary refill was less than 3 seconds and normal turgor. No rash or jaundice was noted with visible cyanosis.

After stabilisation in the delivery room, the infant was taken to the neonatal ICU and was placed on ventilator. Chest x-ray showed dextrocardia with situs inversus (Figure 1). Infant continued to have low oxygen saturations despite ventilatory support with 100% oxygen. Serial blood gases showed persistent hypoxaemia. An urgent echocardiogram (Figure 2) was obtained, which showed a rare association of dextrocardia with transposition of the great vessels (I, L, L-Atrial Inversus/L-loop/L-transposition; mirror image with transposition of the great vessels): [I, L, L] Transposition of Great Arteries. Infant was transferred to level IV neonatal ICU cardiology centre in stable condition for surgical intervention. Genetic testing (CombiSNP Array Analysis) showed interstitial deletion of 22 Mb (megabases) on 5p15.2-p13.3. We did not have further details about the results of single-nucleotide polymorphism array including the extension of the deletion and molecular breakpoints. It will be interesting to map the genes involved in cardiac and laterality development.

Figure 1.

Chest x-ray obtained soon after birth.

Figure 2.

Echocardiogram. (a) Transposition and (b) Doppler study. Ao=aorta; PA=pulmonary artery; PDA=patent ductus arteriosus.

Discussion

Velo-cardio-facial syndrome and conotruncal heart defects have been reported in association with 22q11.2 deletion. Recently, Lejeune et alReference Lejeune, Lafourcade and Berger1 reported isolated heart disease with the same deletion. However, an extensive literature search did not show any reports of association of 5p deletion with dextrocardia and L-transposition of great arteries.

Disorders resulting from 5p deletions (5p–) were first recognised in 1963 by Lejeune et al.Reference Lejeune, Lafourcade and Berger1 The most recognisable phenotype is characterised by a high-pitched cry, dysmorphic features, poor growth, and developmental delay also named as Cri du Chat syndrome.Reference Nguyen, Qualmann, Okashah, Reilly, Alexeyev and Campbell2 The incidence of Cri du Chat syndrome is between 1/15,000 and 1/50,000 live birth. 5p deletions are most commonly de novo occurrences, which are paternal in origin in 80–90% of cases.Reference Mainardi, Perfumo and Cali3 Terminal deletions comprise 80–90% of cases and interstitial deletions account for 3–5%.Reference Mainardi, Pastore and Castronovo4 In the case presented, we noted a significant interstitial deletion of 5p involving a big area from p15.2-p13.3, which includes the CTNND2 gene that has been implicated in the intellectual disability phenotype of Cri du Chat syndrome. Recently, Balta et alReference Balta, Erdogan, Ergul, Sahin and Ozcan5 have reported a case of multiple congenital abnormalities with hypoplastic left heart in association with interstitial deletion of 5p involving an area from p15.2-p14.2.

The critical regions in cases of Cri du Chat syndrome have been mapped to certain symptoms as described in the review by Nguyen et al.Reference Nguyen, Qualmann, Okashah, Reilly, Alexeyev and Campbell2 As far as the association of cardiac defect is concerned, Kondoh et alReference Kondoh, Shimokawa and Harada6 reported six patients with 5p deletion out of which two had CHD. They did not mention the type of CHD in their article; however, the region deleted in CHD was p13.2–p14.1, which is seen in our case as well. Also one of their patients with CHD had talipes that was also noted in our case. Earlier Hills et al,Reference Hills, Moller, Finkelstein, Lohr and Schimmenti7 in a study of 21 patients with Cri du Chat syndrome, reported 6 patients with ventricular septal defect, 6 with patent ductus arteriosus, 5 with tetralogy of Fallot, 2 with pulmonary valve atresia with ventricular septal defect, and 1 each with pulmonary valve stenosis and double-outlet right ventricle. No association with transposition of great arteries was reported. Transposition of great arteries is the most mysterious cyanotic heart disease because it has no precedent in phylogenetic and ontogenetic development and its aetiology and morphogenesis are still largely unknown but was recently related to lateralisation defects.Reference Unolt, Putotto and Silvestri8 While reporting this association, we are not undermining the fact that this could be a coincidental finding but in view of previously described cardiac defect with 5p deletion, further evaluation is warranted.

Not all deletions result in phenotypic manifestations. For example, terminal deletions of 5p in some cases were found to have no phenotypic effects.Reference Bengtsson, Mcmahon and Quarrell9 Similarly, life expectancy varies with presentation and complications. The reported ranges are 36% of deaths in the first month of life and 64% in the first year of life with CHD being one of the most common causes of death.Reference Balta, Erdogan, Ergul, Sahin and Ozcan5 In view of complex heart with known 5p deletion, comfort care was offered to our patient with no escalation in therapy.

In conclusion, interstitial 5p deletion is a rare genetic disease. Our report of association of this with dextrocardia and L-transposition of great arteries is not presented in literature that needs further evaluation.

Acknowledgments

None.

Ethical Standards

All ethical standards were met.

Author ORCIDs

Shabih Manzar 0000-0002-5621-963X

Financial Support

This research received no specific grant from any funding agency, commercial, or not-for-profit sectors.

Conflicts of Interest

None.

References

Lejeune, J, Lafourcade, J, Berger, R, et al. 3 cases of partial deletion of the short arm of a 5 chromosome. C R Hebd Seances Acad Sci 1963; 257: 3098–3102.Google ScholarPubMed
Nguyen, JM, Qualmann, KJ, Okashah, R, Reilly, A, Alexeyev, MF, Campbell, DJ. 5p deletions: current knowledge and future directions. Am J Med Genet C Semin Med Genet 2015; 169: 224–238. doi: 10.1002/ajmg.c.31444 CrossRefGoogle ScholarPubMed
Mainardi, PC, Perfumo, C, Cali, A, et al. Clinical and molecular characterisation of 80 patients with 5p deletion: genotype-phenotype correlation. J Med Genet 2001; 38: 151–158.CrossRefGoogle ScholarPubMed
Mainardi, PC, Pastore, G, Castronovo, C, et al. The natural history of cri du chat syndrome. A report from the italian register. Eur J Med Genet 2006; 49: 363–383.CrossRefGoogle ScholarPubMed
Balta, B, Erdogan, M. Ergul, AB, Sahin, Y, Ozcan, A. Interstitial deletion 5p14.1-p15.2 and 5q14.3-q23.2 in a patient with clubfoot, blepharophimosis, arthrogryposis, and multiple congenital abnormalities. Am J Med Genet A 2017; 173: 2787–2802. doi: 10.1002/ajmg.a.38386 CrossRefGoogle Scholar
Kondoh, T, Shimokawa, O, Harada, N, et al. Genotype-phenotype correlation of 5p–syndrome: pitfall of diagnosis. J Hum Genet 2005; 50: 26–29.10.1007/s10038-004-0213-9CrossRefGoogle Scholar
Hills, C, Moller, JH, Finkelstein, M, Lohr, J, Schimmenti, L.Cri du chat syndrome and congenital heart disease: a review of previously reported cases and presentation of an additional 21 cases from the Pediatric Cardiac Care Consortium. Pediatrics 2006; 117: e924–e927 10.1542/peds.2005-1012CrossRefGoogle ScholarPubMed
Unolt, M, Putotto, C, Silvestri, LM, et al. Transposition of great arteries: new insights into the pathogenesis. Front Pediatr 2013; 1: 11. doi: 10.3389/fped.2013.00011 CrossRefGoogle ScholarPubMed
Bengtsson, U, Mcmahon, J, Quarrell, O, et al. Phenotypically normal carriers of unbalanced terminal deletions of 5p transmit the deletions to offspring who display growth and developmental delay. Am J Hum Genet 1990; 47: A818.Google Scholar
Figure 0

Figure 1. Chest x-ray obtained soon after birth.

Figure 1

Figure 2. Echocardiogram. (a) Transposition and (b) Doppler study. Ao=aorta; PA=pulmonary artery; PDA=patent ductus arteriosus.