Congenital Heart Defects in Sotos Syndrome

Danielle R. Noreau,1 Jamil Al-Ata,2 Luc Jutras,2 and Ahmad S. Teebi1*1Division of Medical Genetics, Montreal Children’s Hospital, McGill University, Montreal, Quebec, Canada2Division of Pediatric Cardiology, Montreal Children’s Hospital, McGill University, Montreal, Quebec, Canada

Sotos syndrome is a relatively commonovergrowth syndrome with characteristicphysiognomy. We report on 3 patients withcongenital heart defects out of 14 Sotos syn-drome patients studied clinically and or byechocardiography. Review showed another17 patients with variable cardiac defects,mostly closure defects, making an overallincidence of approximately 8%. Am. J. Med.Genet. 79:327–328, 1998. © 1998 Wiley-Liss, Inc.

KEY WORDS: overgrowth; echocardio-gram; closure defects

INTRODUCTION

Sotos syndrome was first described by Sotos et al.[1964] in five children with overgrowth and character-istic physiognomy. Since then, over 250 mostly spo-radic cases have been reported. The main clinical find-ing in Sotos syndrome is prenatal and postnatal over-growth. Birth length is usually more significantlyincreased (above the 97th centile) than weight (be-tween the 75th and 97th centiles). Growth is excessivein the first years of life, after which time it proceeds ata relatively normal rate, but consistently falls in thehigh centiles [Sotos, 1997]. Bone age is also signifi-cantly advanced in most cases of Sotos syndrome. It isthought that all cases have advanced bone age at sometime. Head circumference is almost invariably large atbirth, and generally proceeds above the 97th centilethroughout growth. Sotos syndrome patients may alsohave a prominent pointed chin, frontal bossing, hyper-telorism or telecanthus, downslanting palpebral fis-sures, a high arched palate, flat nasal bridge, epican-thic folds, and large hands and feet. Mild to moderatedevelopmental delay is present, often with behaviourproblems, and an emotional immaturity that persistsinto adulthood [Cole and Hughes, 1990]. There is evi-dence of an increased incidence of additional anomaliessuch as neonatal jaundice and feeding difficulties,

clumsiness and incoordination, seizures [Cole andHughes, 1990], and formation of solid tumours (Wilmstumour, hepatic tumours) [Hersh et al., 1992].

Congenital heart defects (CHDs) have been reportedin Sotos syndrome patients. In a study from Japan, 5 of10 Japanese patients were found to have various CHDs[Kaneko et al., 1987]. In another study from England 5patients out of 40 had heart defects [Cole and Hughes,1994]. In other reports, there was no mention of heartdefects in Sotos syndrome. Here we report CHDs in 14patients with Sotos syndrome and review the literaturepertaining to similar cases.

PATIENTS AND METHODSAll 14 patients (9 females and 5 males) had been seen

in the Medical Genetic clinics at the Montreal Chil-dren’s Hospital. Diagnostic criteria included advancedbone age, overgrowth, characteristic facial gestalt withor without developmental delay, and exclusion of otherovergrowth syndromes. Department and hospital re-cords were reviewed on all 14 patients, and data on thefollowing were collected for each: birth weight, birthlength, mode of delivery, neonatal problems, age at di-agnosis, craniofacial characteristics, bone age, develop-ment, karyotype, Fragile X testing, and computed to-mographic scan and/or magnetic resonance imagingfindings. Collection of data on craniofacial characteris-tics included noting the presence or absence in eachpatient of macrocephaly, hypertelorism or telecanthus,prominent chin, prominent forehead, downslantingpalpebral fissures, epicanthic folds, flat nasal bridge,high arched palate, large hands, and large feet.

All 14 patients included in this study were foundpreviously to have advanced bone age through radio-logical studies conducted at or near the time of referral.Of these, 12 had a chromosome analysis with normalresults and 9 had FMR-1 testing with normal results.

Three patients were known to have CHDs. For thepurpose of the study we decided to perform cardiologi-cal evaluation in all patients including clinical andechocardiographic examinations. An echocardiogramwas performed on 11 of the 14 patients including thosepreviously known to have heart defects. The family ofone patient declined an echocardiogram; the families oftwo other patients could not be contacted.

RESULTSThe age of diagnosis of our patient group ranged

from 4 months to 15 years. Clinical manifestations, in-

*Correspondence to: Ahmad S. Teebi, M.D., Division of ClinicalGenetics,Hospital for Sick Children and University of Toronto,555 University Avenue, Toronto, Ontario, M5G 1X8, Canada.E-mail: ateebi@sickkids.on.ca

Received 27 April 1998; Accepted 8 June 1998

American Journal of Medical Genetics 79:327–328 (1998)

© 1998 Wiley-Liss, Inc.

cluding craniofacial characteristics, in our patientswith Sotos syndrome were comparable to those re-ported previously. Manifestations noted in our patientsthat are not commonly found in Sotos syndrome in-cluded anisocoria, macroglossia, non-functional leftkidney, shawl scrotum, unilateral cryptorchidism, andleft Poland anomaly. Hormonal problems and malig-nancies were absent in all of our patients.

Three patients known to have CHDs included onesmall ventricular septal defect (VSD) that closed spon-taneously, a patent ductus arteriosus (PDA), whichwas repaired, and an aorto-pulmonary window whichwas surgically closed at age 3 months. Echocardio-grams performed on eight patients did not show anyadditional cases of heart disease. The remaining threepatients with no echocardiograms done had no clinicalevidence of heart problems.

DISCUSSION

Over 250 individuals with Sotos syndrome have beenreported. Of these, 17 have been reported to have aCHD. Zonana et al. [1977] reported on one patient witha midsystolic murmur at the upper left sternal border.Wilson et al. [1980] reported on one patient with a VSDthat closed spontaneously. Kaneko et al. [1987] re-ported on five patients with CHDs; two with an atrialseptal defect (ASD), and one patient each with PDAwith mitral valve regurgitation, tricuspid atresia pluspulmonary atresia, and VSD. DiMarco et al. [1989] de-scribed one patient with aortic and mitral valve mal-

formations. Tantam et al. [1990] described one patientwith evidence of Sotos syndrome to have increased aor-tic compliance. Yanagisawa et al. [1991] reported onone patient with secundum type ASD. Moore andByard [1992] described one patient with a VSD andmild pulmonary stenosis. Haeusler et al. [1993] re-ported one patient who had obstructive hypertrophiccardiomyopathy and a type II ASD. Cole and Hughes[1994] described five patients with CHDs; four patientswith PDA (one of which also had pulmonary stenosis),and one patient with an ASD. Table I summarises theknown 20 patients having Sotos syndrome with CHDsincluding the present patients. This makes the inci-dence of CHDs in Sotos syndrome approximately 8%,which is roughly a 10-fold increase over the populationincidence of 0.6 to 1.0% [Nora et al., 1991].

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DiMarco G, Levantesi G, Parisi G, Chiarelli A (1989): [Congenital cardi-opathy in a patient with Sotos syndrome. Description of a case]. G ItalCardiol 19:453–455.

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Kaneko H, Tsukahara M, Tachibana H, Kurashige H, Kuwano A, Kajii T(1987): Congenital heart defects in Sotos sequence. Am J Med Genet26:569–576.

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TABLE I. CHD in Patients With Sotos Syndrome Reported toDate, Including Our Three Patients*

CHDNumber of

patients

ASD 4VSD 3PDA 4‘‘Midsystolic murmur’’ 1Aorto-pulmonary window 1Increased aortic compliance 1PDA + mitral valve regurgitation 1ASD + hypertrophic cardiomyopathy 1VSD + pulmonary stenosis 1PDA + pulmonary stenosis 1Tricuspid atresia + pulmonary atresia 1Malformations of aortic valve + mitral valve 1Total 20

*ASD, atrial septal defect; VSD, ventricular septal defect; PDA, patentductus arteriosus.

328 Noreau et al.