American Journal of Medical Genetics 116A:234–237 (2003)

Prevalence of Mitral Valve Prolapsein Stickler Syndrome

Nadeem Ahmad,1 Allan J. Richards,2 Helen C. Murfett,3 Leonard Shapiro,3 John D. Scott,1

John R.W. Yates,4 Joanne Norton,3 and Martin P. Snead1*1Department of Ophthalmology, Vitreoretinal Service, Addenbrooke’s Hospital, Cambridge, UK2Department of Pathology, University of Cambridge, Cambridge, UK3Department of Cardiology, Addenbrooke’s Hospital, Cambridge, UK4Department of Medical Genetics, Addenbrooke’s Hospital, Cambridge, UK

The prevalence of mitral valve prolapse inStickler syndrome has been reported to bemuch higher than in the general population.As a result, it has been recommended that allpatients with Stickler syndrome undergoroutine echocardiography and have antibio-tic prophylaxis prior to surgery. The purposeof this study was to evaluate the prevalenceof mitral valve prolapse in a large cohort ofUK patients with Stickler syndrome in whomthe clinical diagnosis has been confirmed bymolecular genetic analysis. Probands andpedigrees were identified from the Vitreor-etinal Service database according to pre-viously published criteria. Ophthalmic,skeletal, audiometric, and orofacial featureswere assessed. Affected individuals under-went a full cardiological examination in-cluding auscultation and two-dimensionalechocardiography. Mutation analysis of theCOL2A1andCOL11A1genes was carried out.Seventy-eight patients from 25 pedigreeswere studied. Mutation analysis confirmedthe clinical diagnosis in every pedigree. Nopatient was found to have clinical evidenceof cardiovascular disease and no patient hadsignificant mitral or other valvular prolapseon echocardiography. These data from alarge cohort of UK patients with provenStickler syndrome do not suggest an increas-ed incidence of mitral valve prolapse over

and above that found in the general popula-tion. Routine echocardiography screeningand use of preoperative antibiotics areunnecessary and should be reserved forthose individual cases where there is clearclinical indication. � 2002 Wiley-Liss, Inc.

KEY WORDS: COL2A1; mitral valve pro-lapse; echocardiography;Stickler syndrome; vitreous

INTRODUCTION

Stickler syndrome [Hereditary Arthro-ophthalmopa-thy, MIM 108300 and 184840] is a dominantly inheriteddisorder of collagen connective tissue, resulting inabnormalities of vitreous, myopia, retinal detachment,midfacial hypoplasia, midline clefting, deafness, andarthropathy [Stickler et al., 1965; Stickler and Pugh,1967]. Mutations have been identified in COL2A1 andCOL11A1, the genes for types II andXI collagen [Ahmadet al., 1991; Richards et al., 1996]. Systemic features arehighly variable [Snead and Yates, 1999; Richards et al.,2000a,b; Snead et al., 2000].

Stickler syndrome is the commonest inherited causeof rhegmatogenous retinal detachment in childhood,with a high risk of giant retinal tear, which can bebilateral. As a result, patients frequently present to thevitreoretinal surgeon either for prophylactic cryother-apy or with complex retinal detachment requiringurgent surgery under general anesthesia. In addition,patients commonlyundergo elective surgical proceduresrequiring general anesthesia to treat a variety oforthopedic, oro-facial and middle ear disorders.

The prevalence of mitral valve prolapse in Sticklersyndrome has been reported to be much higher than inthe general population [Liberfarb and Goldblatt, 1986].This has been attributed to the generalized abnormalityaffecting the connective tissues, comparable to otherdisorders such as Marfan syndrome, Ehlers-Danlossyndrome, and pseudoxanthoma elasticum [Leier et al.,1980; Pini et al., 1989]. It has therefore been recom-mended that all patients with Stickler syndrome under-

Grant sponsor: Guide Dogs for the Blind Association; Grantsponsor: Stanley Thomas Johnson Foundation; Grant sponsor:Isaac Newton Trust; Grant sponsor: University of CambridgeRetinal Research Fund.

*Correspondence to: Martin P. Snead, Vitreoretinal Service,Box 41, Addenbrooke’s Hospital, Hills Road, Cambridge CB2 2QQ,UK. E-mail: mps34@cam.ac.uk

Received 9 November 2001; Accepted 17 April 2002

DOI 10.1002/ajmg.a.10619

� 2002 Wiley-Liss, Inc.

go routine cardiac evaluation including echocardiogra-phy [Liberfarb and Goldblatt, 1986], and that in thesepatients, antibiotic prophylaxis prior to surgery shouldbe considered [Liberfarb and Goldblatt, 1986; Temple,1989]. Since these early reports, the clinical andmolecular genetic heterogeneity of Stickler syndromehas been more clearly defined [Snead et al., 1994;Ballo et al., 1998; Annunen et al., 1999; Martinet al., 1999; Snead and Yates, 1999; Richards et al.,2000a,b]. In the light of this data, the purpose of thisstudy was to examine the prevalence of mitral valveprolapse in a large cohort of patients satisfying un-equivocal clinical and genetic diagnostic criteria forStickler syndrome.

METHODS

Probands and pedigrees were identified from the Vit-reoretinal Service database at Addenbrooke’s Hospital.Ophthalmic, skeletal, audiometric, and orofacial fea-tures were assessed using the methods previouslyreported [Richards et al., 2000a]. Informed writtenconsent was obtained from all patients and prior ethicalapproval for the study was received (LREC92/019).

A direct inquiry was made regarding the cardiovas-cular status of all patients. Seventy-four patients wereable to appear for cardiology assessment, and allunderwent a full cardiological examination includingauscultation and two-dimensional echocardiography.Echocardiographic studies were carried out at the de-partment of Cardiology Addenbrooke’s NHS Trust

Cambridge, using a Hewlett-Packard Sonos 2500(63 scans) and Sonos 4500 (15 scans) with 3.5–2.5 MHzphased-array transducers. Echocardiographic viewsconsisted of long and short axis, apical four and apicaltwo chambers, incorporating conventional pulsed andcolor flow Doppler. Mitral valve prolapse was definedaccording to the established criteria of systolic displace-ment of themitral leaflets bymore than twomm into theleft atrium superior to themitral annular plane (the lineconnecting the annular hinge points of the leaflets).

Molecular Genetic Analysis

Mutation analysis of cDNA for a1(XI) collagen wasperformedasdescribedpreviously [Richards et al., 1996;Martin et al., 1999]. Mutations in COL2A1 were de-tected by amplification and exon sequencing as alsopreviously described [Richards et al., 2000a]. Mutationswere confirmed by analyzing DNA from all family mem-bers, either by restriction enzymes digestion, or singledideoxynucleotide sequencing reactions [Richards et al.,1996, Richards et al., 2000a,b].

RESULTS

One hundred and fifteen affected patients wereidentified from25pedigrees.Mutation analysis confirm-ed the clinical diagnosis. The pedigrees and mutationanalysis are summarized in Table I. A mixture of mis-sense, premature termination codons, frame shift, andsplicing mutations were found. Some of these have been

TABLE I. Summary of Results

Family no. Gene Mutation ReferenceNumberaffected

Echocardio-gram performed

MS1 COL11A1 G97V Richards et al. [1996] 7 4MS2 COL2A1 PTC R585X Richards et al. [2000a] 3 3MS4 COL2A1 Missplice IVS51 Gþ 1T — 4 4MS5 COL2A1 PTC Q1037X — 3 5MS6 COL2A1 Missplice IVS51 Tþ 2C — 5 1MS8 COL2A1 22621 1 bp ins (C) Exon 36 Richards et al. [2000a] 1 1MS11 COL2A1 4267 4 bp ins (GGAT) Exon 2 Richards et al. [2000a] 8 4MS12 COL2A1 R365C Richards et al. [2000b] 1 1MS15 COL2A1 Missplice IVS 27 Gþ1A — 5 4MS17 COL2A1 27870 1 bp ins (G) Exon 49 Richards et al. [2000a] 5 4MS19 COL2A1 Missplice IVS 23 Gþ135A — 10 9MS20 COL2A1 PTC R732X Richards et al. [2000a] 6 3MS22 COL2A1 Missplice IVS 40 Gþ5C — 2 2MS23 COL2A1 Missplice IVS 50 Tþ2G — 9 2MS24 COL2A1 27852 1 bp del (A)/8 bp ins (TCCTGCTG) Exon 49 — 1 1MS25 COL2A1 L467F Richards et al. [2000b] 9 5MS31 COL2A1 PTC R453X — 3 2MS39 COL2A1 26312 (G) bp del Exon 44 — 3 2MS40 COL11A1 Multi Exon Deletion (31–42) Martin et al. [1999] 10 7MS42 COL11A1 Missplice IVS 14 A�2 del Martin et al. [1999] 5 1MS51 COL2A1 Missplice IVS 29 Gþ1A — 4 4MS54 COL2A1 17189 1 bp del (T) Exon 21 — 2 2MS55 COL2A1 PTC 687X — 2 2MS66 COL2A1 25673 1 bp ins (C) Exon 42 Richards et al. [2000a] 3 3MS96 COL2A1 26313 1 bp ins (A) Exon 37 — 4 2Total 115 78

Position of insertions (ins) or deletions (del) in COL2A1 are located by the nucleotide number in the complete gene sequence (accession No. L10347).Premature termination codons (PTC) are indicated by the altered amino acid in the procollagenmolecule, where the first glycine of the triple helical region isnumbered as 1. Amino acid substitutions are likewise indicated. For COL2A1 the exons are numbered 1–54.

Mitral Valve Prolapse in Stickler Syndrome 235

reported previously (as indicated). Clinical examinationrevealed no evidence of cardiovascular disease. None ofthe 78 patients assessed by echocardiography hadsignificant mitral or other valvular abnormality.

DISCUSSION

Although most patients with mitral valve prolapsehave a benign clinical course [Panidis et al., 1986;Devereux, 1995], the presence of a valvular defect, espe-cially when associated with regurgitation, puts thepatient at higher risk of various peri- and postope-rative complications, including bacterial endocarditis[MacMahon et al., 1987; Devereux, 1995]. Any patientwith a suspicion of such a valve abnormality needsprophylactic antibiotics when undergoing any surgicalprocedure.

Mitral valve prolapse is a condition that can havepotentially serious complications including stroke,heart failure, atrial fibrillation, and severe mitralregurgitation [Devereux, 1995]. The frequency of diag-nosis of mitral valve prolapse (MVP) depends upon thediagnostic criteria used. Initial echocardiographic defi-nitions suggested a high prevalence in otherwisenormal individuals [Sasaki et al., 1982; Wann et al.,1983; Warth et al., 1985; Morganroth et al., 1980]. Morerecently, revised echocardiographic diagnostic criteriahave returned MVP to a relatively infrequent condition[Levine et al., 1988]. It has also been recommended thatpatients previously diagnosed with mitral valve pro-lapse should have repeat echocardiography to confirmthis diagnosis [Panidis, 1996].

Initial studies suggested a high prevalence of MVP inpatients with Stickler syndrome [Liberfarb and Gold-blatt, 1986] but this might reflect a higher rate of falsepositives resulting from diagnostic criteria which havesince been revised [Levine et al., 1988]. In addition, it ispossible that earlier studies could have included a moreheterogenous group of connective tissue disorderswhereMVP can occur, sincemolecular genetic diagnosisfor Stickler syndromewas not possible at that time. Ourresults from a large cohort of UK patients with provenStickler syndrome do not confirm this finding, suggest-ing that the prevalence of mitral valve prolapse inpatients with Stickler syndrome is similar to that in thenormal population. Routine echocardiography screen-ing and use of preoperative antibiotics are thereforeunnecessary and should be reserved for those individualcases where there is clear clinical indication. This willnot only reduce the cost of treatment and the workloadon the cardiology services, butwill also ensure that thereis no unnecessary delay in the urgent surgery that thesepatients sometimes require for retinal reattachment. Itis also reassuring for the patients with Sticklersyndrome that their risk of valvular heart disease issimilar to the general population.

ACKNOWLEDGMENTS

We gratefully acknowledge the help of The SticklerSyndrome Support Group and Mrs. Gillian Whitmoreand Mrs. Dawn Kelly, Vitreoretinal Service co-coordi-nators, Addenbrooke’s Hospital.

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