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Year : 2018  |  Volume : 7  |  Issue : 1  |  Page : 54-58

Vascular ring and ventricular septal defect in a premature baby with smith–magenis syndrome

1 Department of Paediatrics, University of Tasmania, Tasmania, Australia
2 Department of Paediatrics, North West Regional Hospital, Tasmania, Australia

Date of Web Publication6-Feb-2018

Correspondence Address:
Dr. Anutosh Shee
University of Tasmania, 21 Brickport Rd, Cooee Tasmania 7320
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jcn.JCN_72_17

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Clinical detection of genetic disorders in early neonatal period is often difficult, particularly in the context of difficulty in recognizing subtle facial dysmorphism in prematurity. As the newer technology such as phenotype-based whole-exome sequencing is gaining popularity as the most effective and reliable way of early diagnosis more emphasis will be returned back to identify typical and uncommon phenotypical features of genetic disorders. Smith–Magenis syndrome (SMS) is a sporadic genetic disorder caused by 17p11.2 microdeletion in 90% of cases with wide variety of features ranging from intellectual disability, distinctive facial appearance, significant circadian sleep rhythm abnormality, congenital heart disease (CHD) (30%), brain and renal malformation to obvious behavioral problems, most of which, however, are appreciable only at late childhood. Currently, SMS is diagnosed by single-nucleotide polymorphism microarray. Earlier diagnosis for this sporadic condition depends on high index of suspicion, particularly for those who are missed during the fetal morphology scan. CHD can be a very important clue in the fetal or early neonatal period. In this article, we present a preterm infant with SMS in association with ventricular septal defect and vascular ring, a combination of which was not reported earlier. Notification of these atypical features is an important element of increasing the knowledge base in the process of the earlier diagnosis in future.

Keywords: Central nervous system, congenital heart disease, copy number variant, intra-uterine growth restriction, patent ductus arteriosus, single-nucleotide polymorphism microarray (SNP microarray), Smith–Magenis syndrome, tetralogy of Fallot, ultrasound scan, ventricular septal defect, atrial septal defect

How to cite this article:
Shee A, Nayan-Cruz J. Vascular ring and ventricular septal defect in a premature baby with smith–magenis syndrome. J Clin Neonatol 2018;7:54-8

How to cite this URL:
Shee A, Nayan-Cruz J. Vascular ring and ventricular septal defect in a premature baby with smith–magenis syndrome. J Clin Neonatol [serial online] 2018 [cited 2022 May 19];7:54-8. Available from: https://www.jcnonweb.com/text.asp?2018/7/1/54/224813

  Introduction Top

Smith–Magenis syndrome (SMS) is a complex developmental disorder with a wide variety of phenotypical features including mild-to-moderate intellectual disability, delayed speech and language development, distinctive facial features, significant circadian sleep rhythm abnormality, congenital heart disease (CHD), brain and renal malformation, hypothyroidism, low immunoglobulin levels, abnormal lipid profile, forearm deformities, and some nonspecific and typical behavioral problems.[1] SMS occurs due to either interstitial microdeletion of chromosome 17p11.2 in 90% of cases or mutation in RAI1 gene for the rest. The true prevalence of SMS may be as high as 1 in 15000 individuals, though most cases remain undiagnosed in the community. Almost all the cases of SMS are sporadic occurring as a de novo mutation. CHD is seen in nearly 30% cases of SMS. The most common defects are ventricular septal defect (VSD), atrial septal defect (ASD), and tetralogy of Fallot (TOF).[2] Distinctive facial features seen in children consist of broad, square-shaped face with deep-set of eyes, full cheeks, and a prominent lower jaw. These are often extremely difficult to identify in the early neonatal period, particularly in prematurity, however, usually become more obvious in late childhood. Other signs and symptoms of SMS include short stature, scoliosis, reduced sensitivity to pain and temperature and hoarse voice, refractive errors, and deafness. In this article, we present a unique case of SMS associated with complex cardiac anomaly including vascular ring, not being reported in the past to the best of our knowledge.[3]

  Case Report Top

A preterm baby girl weighing 1636 gm was born at 34 weeks of gestation by cesarean section due to of intrauterine growth restriction (IUGR). She was the second child to her nonconsanguineous parents with one previous healthy living child. Antenatal ultrasound scan showed severe IUGR, oligohydramnios, right-sided aortic arch, and aberrant left subclavian artery. She was detected to have soft systolic murmur in the neonatal intensive care unit but remained hemodynamically stable without needing any respiratory support. Postnatal echocardiogram confirmed the presence of moderately large and mildly restrictive perimembranous VSD (4–5 mm) with high-velocity left-to-right shunt [Figure 1]. There was slightly dilated left atrium with bulging of interatrial septum toward the right atrium in the presence of patent foramen ovale. Postnatal echocardiogram also confirmed aberrant left subclavian artery which in the presence of right-sided aortic arch conform the vascular ring. There was no evidence of pulmonary hypertension. She did not have any stridor or feeding intolerance. She was discharged home on oral diuretics at 4 weeks while waiting for the definitive cardiac surgery. SNP microarray analysis revealed a female molecular karyotype with an approximately 3.6 megabase deletion of chromosome 17 at cytogenetic band 17p11.2 (by Illumina Infinium CoreExome-24 v1.1, resolution 0.20 Mb) suggestive of SMS [Figure 2] and [Figure 3].
Figure 1: Left pane: Two-dimensional image from apex, RV . Right ventricle; LV . Left ventricle; VSD . Ventricular septal defect; Ao . Ascending aorta; Right pane color flow across VSD showing left-to-right shunt(Echocardiography)

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Figure 2: Entire short arm of chromosome 17 and just below the centromere with the smooth log R and the B-allele frequency results(SNP microarray)

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Figure 3: Region of 17p11-12, 17 centromere and part of the long arm with the log R, smoothed log R, and the B-allele frequency results(SNP microarray)

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  Discussion Top

SMS was first described in 1986 by Smith et al. in nine unrelated cases associated with strikingly similar phenotypes.[3] Many more have been reported down the line, including few of them diagnosed prenatally by amniocentesis with single-nucleotide polymorphism (SNP) microarray.[4] Variability in the phenotype of SMS might be related to the impact of incomplete penetrance and involvement of the variable genes in the region of 17p11.2. A small percentage of people (10%) with SMS have mutation only in the RAI1 gene instead of a complete 17p11.2 deletion.[1],[2],[3] They are less likely to have short stature, deafness, and heart or kidney abnormalities but classically, more likely to exhibit overeating, obesity, and self-hugging behavior.[2],[5] Structural malformations such as heart and renal defects probably occur due to hemizygosity of other genes in the 17p11.2 region. Among these, another important gene deletion noted in most cases of SMS is sterol regulatory element binding protein 1 (SREBF1) gene for a transmembrane transcription factor which regulates the LDL receptor involved in cholesterol homeostasis.[6] This is believed to be a potential cause of abnormal lipid profile seen in adolescents or young adults with SMS. Overall, 30%–40% of children with SMS have systemic manifestations including the cardiac, renal, and central nervous system abnormalities.[1],[2],[3],[4] Among the cardiac anomalies VSD, ASD, tricuspid stenosis, mitral stenosis, tricuspid, mitral regurgitation, aortic stenosis, pulmonary stenosis, mitral valve prolapse, TOF, and total anomalous pulmonary venous return [Table 1] have been reported in varying combination in nearly 30% of cases of SMS.[3],[7] In our case, the right-sided aortic arch was evident since the 20 weeks fetal morphology scan. Right aortic arch, which can be a normal variant, is defined as an aortic arch that crosses the right bronchus instead of the left bronchus and the ductus arteriosus passes either to the right or left of the trachea to join the aortic arch. It is, however, present more frequently in association with other intra- and/or extra-cardiac defects such as TOF, trisomy 21 and 22q11 microdeletion syndrome. Right-sided aortic arch in the context of SMS has previously been reported only once in a 16-week fetus which ended up in termination.[4] In our case, however, additional feature, that is, aberrant left subclavian artery has led to the formation of the vascular ring. This has the potential to compress the trachea causing stridor, respiratory distress, and feeding difficulty. However, this infant remained asymptomatic from the vascular ring point of view.
Table 1: Previously reported congenital heart diseases associated with Smith–Magenis syndrome

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Clinical detection of genetic disorders in early neonatal period is often difficult, particularly in the context of difficulty in recognizing subtle facial dysmorphism in prematurity, often leading to significant delay in the diagnosis. This may impact on the prognosis, triaging of cardiac surgery, and on parental expectation. With the advancement of fetal medicine, more and more CHDs are diagnosed in utero. CHD can be isolated or associated with extracardiac malformations, which may or may not be obvious on the antenatal morphology scan.[4] Routine microarray in amniocentesis can add valuable information for the counseling, therefore, help informing parents about the prognosis earlier. SNP microarray has been developed as a genome-wide screening strategy for detecting DNA copy number variants and used as the first-line test in the initial evaluation of individuals with developmental delay, autism, and multiple congenital anomalies.[12] SMS is hypothesized to be a contiguous gene syndrome in which haploinsufficiency of one or more genes (38–70 genes) that lie within the critical interval is likely to be responsible for the SMS phenotype, although the true molecular basis of SMS, particularly the causation of CHD is still not known.[12],[13] Interestingly, when the reciprocal microduplication is seen in the same region instead of deletion it is called Potocki–Lupski syndrome which is a developmental disorder characterized by hypotonia, failure to thrive, learning disability, autism, and congenital anomalies. In microduplication, all reported cases have occurred sporadically without bias in the parental origin of rearrangements.[13],[14],[15]

There are certain clinical features, when present in infants and children, can potentially alarm the clinicians about the underlying diagnosis of SMS. Children with SMS often have affectionate, engaging personalities, but most also have behavioral problems. These include frequent temper tantrums, aggression, anxiety, and attention-deficit/hyperactivity-like symptoms. Self-injury, including biting, hitting, head banging, and skin picking are very common. Repetitive self-hugging is a behavioral trait that is quite unique to SMS. Disrupted sleep patterns are characteristic of SMS, typically beginning early in life with reversed sleep-wake cycle in the day and night time. This could be secondary to aberrations in the production, secretion, distribution, or metabolism of melatonin.[15] There are clinical trials going on about the effectiveness of melatonin on SMS. However, for neonates, these features are not present. Structural malformations such as CHD detected at the time of fetal or neonatal echocardiography often provide valuable clue in a subset of SMS. There is no pathognomonic type of CHDs seen in SMS. Various case reports have identified different types of CHDs in SMS, which are present in higher number than the general population.[8],[9],[10],[11],[16],[17],[18] The knowledge about the typical and newly recognized CHDs seen in SMS is, therefore, very important for the clinicians to have higher index of suspicion before considering SNP microarray or phenotype-based whole-exome sequencing. The CHDs in SMS often necessitate open-heart surgery early in life and may require further surgery later in life. There is no systematic reviews available about the outcomes of cardiac surgeries in children with SMS. At the moment, few case reports suggest that the outcome may be essentially dependent on to the primary cardiac anomalies. Complications such as the need for repeat open heart surgery and postoperative stroke were reported in an adult with SMS after successful early childhood repair of ASD, VSD, and pulmonary stenosis when she was 4 years old.[6] People with SMS otherwise have normal life expectancy, and premature atherosclerosis can be a major contributor of the cardiac comorbidities. Fasting lipid profiles in children with SMS have shown that 57% of SMS patients had lipid values greater than the 95th percentile for age and sex.[19] This may serve as a useful early biochemical marker of the syndrome. Although, further studies are required, it will not be unreasonable for people with SMS to be evaluated for possible premature cerebrovascular disease prior to the surgery. Whether earlier commencement of statins in this cohort of population can delay any adverse cardiac outcome, that needs to be investigated.

  Conclusion Top

This case has added value to the awareness of another atypical type of CHD to the already existing list of common heart defects associated with SMS. Although, further case reports are necessary before an association can be established between these two, the echocardiographic finding of this uncommon and atypical CHD in a neonate could prompt the treating clinicians to consider a possible underlying genetic condition such as SMS, therefore, helping them to inform parents about the future prognosis early, specifically about the highly likelihood of learning disability. This information can be helpful in triaging of children waiting for the cardiothoracic surgery in the resource-poor settings. The presence of vascular ring in the fetal echocardiography even in the absence of other extracardiac malformation can motivate pregnant women to accept the offer of amniocentesis and SNP microarray testing. This case also adds value to the clinicians' awareness about the recognition of another possible phenotypic association of SMS and, therefore, has the potential to apply exome sequencing for earlier diagnosis in selected cases. A further systematic review is necessary to explore the diagnostic yield of underlying genetic disorder based on the SNP microarray profile of children with isolated and syndromic CHDs.

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Conflicts of interest

There are no conflicts of interest.

  References Top

Greenberg F, Lewis RA, Potocki L, Glaze D, Parke J, Killian J, et al. Multi-disciplinary clinical study of Smith-Magenis syndrome (deletion 17p11.2). Am J Med Genet 1996;62:247-54.  Back to cited text no. 1
Edelman EA, Girirajan S, Finucane B, Patel PI, Lupski JR, Smith AC, et al. Gender, genotype, and phenotype differences in Smith-Magenis syndrome: A meta-analysis of 105 cases. Clin Genet 2007;71:540-50.  Back to cited text no. 2
Smith AC, McGavran L, Robinson J, Waldstein G, Macfarlane J, Zonona J, et al. Interstitial deletion of (17)(p11.2p11.2) in nine patients. Am J Med Genet 1986;24:393-414.  Back to cited text no. 3
Lei TY, Li R, Fu F, Wan JH, Zhang YL, Jing XY, et al. Prenatal diagnosis of Smith-Magenis syndrome in two fetuses with increased nuchal translucency, mild lateral ventriculomegaly, and congenital heart defects. Taiwan J Obstet Gynecol 2016;55:886-90.  Back to cited text no. 4
Slager RE, Newton TL, Vlangos CN, Finucane B, Elsea SH. Mutations in RAI1 associated with Smith-Magenis syndrome. Nat Genet 2003;33:466-8.  Back to cited text no. 5
Chaudhry AP, Schwartz C, Singh AK. Stroke after cardiac surgery in a patient with Smith-Magenis syndrome. Tex Heart Inst J 2007;34:247-9.  Back to cited text no. 6
Abuhamad AZ, Chaoui R. A Practical Guide to Fetal Echocardiography Normal and Abnormal Hearts. 2nd ed. Philadelphia, Pennsylvania: Lippincott Williams & Wilkins; 2010.  Back to cited text no. 7
Myers SM, Challman TD. Congenital heart defects associated with Smith-Magenis syndrome: Two cases of total anomalous pulmonary venous return. Am J Med Genet A 2004;131:99-100.  Back to cited text no. 8
Yamamoto T, Ueda H, Kawataki M, Yamanaka M, Asou T, Kondoh Y, et al. A large interstitial deletion of 17p13.1p11.2 involving the Smith-Magenis chromosome region in a girl with multiple congenital anomalies. Am J Med Genet A 2006;140:88-91.  Back to cited text no. 9
Huang C, Yang YF, Zhang H, Xie L, Chen JL, Wang J, et al. Microdeletion on 17p11.2 in a Smith-Magenis syndrome patient with mental retardation and congenital heart defect:First report from China. Genet Mol Res 2012;11:2321-7.  Back to cited text no. 10
Shen LX, Zhang JS, Ji X, Xing Y, Hu J, Tao J, et al. Clinical and genetic study of a case with Smith-Magenis syndrome. Zhonghua Er Ke Za Zhi 2012;50:227-30.  Back to cited text no. 11
Thomas DG, Jacques SM, Flore LA, Feldman B, Evans MI, Qureshi F, et al. Prenatal diagnosis of Smith-Magenis syndrome (del 17p11.2). Fetal Diagn Ther 2000;15:335-7.  Back to cited text no. 12
Kallioniemi A, Kallioniemi OP, Sudar D, Rutovitz D, Gray JW, Waldman F, et al. Comparative genomic hybridization for molecular cytogenetic analysis of solid tumors. Science 1992;258:818-21.  Back to cited text no. 13
Lucas RE, Vlangos CN, Das P, Patel PI, Elsea SH. Genomic organisation of the approximately 1.5 mb Smith-Magenis syndrome critical interval: Transcription map, genomic contig, and candidate gene analysis. Eur J Hum Genet 2001;9:892-902.  Back to cited text no. 14
Shchelochkov OA, Cheung SW, Lupski JR. Genomic and clinical characteristics of microduplications in chromosome 17. Am J Med Genet A 2010;152A:1101-10.  Back to cited text no. 15
Potocki L, Glaze D, Tan DX, Park SS, Kashork CD, Shaffer LG, et al. Circadian rhythm abnormalities of melatonin in Smith-Magenis syndrome. J Med Genet 2000;37:428-33.  Back to cited text no. 16
Sanford EF, Bermudez-Wagner K, Jeng LJ, Rauen KA, Slavotinek AM. Congenital diaphragmatic hernia in Smith-Magenis syndrome: A possible locus at chromosome 17p11.2. Am J Med Genet A 2011;155A:2816-20.  Back to cited text no. 17
Li Z, Shen J, Liang J, Sheng L. Congenital scoliosis in Smith-Magenis syndrome: A case report and review of the literature. Medicine (Baltimore) 2015;94:e705.  Back to cited text no. 18
Smith AC, Gropman AL, Bailey-Wilson JE, Goker-Alpan O, Elsea SH, Blancato J, et al. Hypercholesterolemia in children with Smith-Magenis syndrome: Del (17) (p11.2p11.2). Genet Med 2002;4:118-25.  Back to cited text no. 19


  [Figure 1], [Figure 2], [Figure 3]

  [Table 1]


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