Further Delineation of the Opitz G/BBB Syndrome:Report of an Infant With Complex Congenital HeartDisease and Bladder Exstrophy, and Review ofthe Literature

Zev Jacobson,1* Julie Glickstein,2 Terry Hensle,3 and Robert W. Marion4

1Department of Pediatrics, Montefiore Medical Center/Albert Einstein College of Medicine, Bronx, New York2Division of Pediatric Cardiology, Montefiore Medical Center/Albert Einstein College of Medicine, Bronx, New York3Division of Pediatric Urology, Columbia-Presbyterian Medical Center/Columbia University College of Physiciansand Surgeons, New York, New York

4Division of Genetics, Montefiore Medical Center/Albert Einstein College of Medicine, Bronx, New York

The combination of complex congenitalheart disease (double outlet right ventriclewith pulmonary atresia, malalignment ven-triculoseptal defect, right-sided aortic archwith left ductus arteriosus) and bladder ex-strophy occurred in an infant with Opitzsyndrome. Neither of these defects haspreviously been reported in associationwith Opitz syndrome. These malforma-tions, which are midline defects, furthercharacterize this syndrome as an impair-ment in midline development. The spectrumof congenital heart disease and genitouri-nary anomalies seen in Opitz syndrome isreviewed. Am. J. Med. Genet. 78:294–299,1998. © 1998 Wiley-Liss, Inc.

KEY WORDS: Opitz G/BBB syndrome; com-plex congenital heart dis-ease; bladder exstrophy

INTRODUCTION

First described in 1969 by Opitz et al. [1969a,b] theOpitz G/BBB syndrome (OS) is a disorder character-ized by hyperterlorism, hypospadias and other midlineanomalies. We describe a patient with OS who wasfound to have complex congenital heart disease, includ-ing double-outlet right ventricle; a malaligned ven-triculoseptal defect (VSD); pulmonary atresia; right-sided aortic arch and a left-sided, tortuous ductus ar-teriosus; and bladder exstrophy, anomalies that havenot been previously reported in this disorder. This case

adds to the list of midline anomalies previously de-scribed in OS and further supports the characteriza-tion of OS as a development defect in the midline field.

CLINICAL REPORT

The propositus was the product of a full-term gesta-tion born by spontaneous vaginal delivery to a 26-yearold gravida 2 para 1 woman and a 28-year old man. Theparents, who were both born in the United States, arenot known to be consanguineous. Their previous childis in excellent health. There is no history of twinning,clefting, hypertelorism, or hypospadias in any first- orsecond-degree relatives.

At the time of delivery, a tight nuchal cord wasnoted. The Apgar scores were 1, 4, and 6 at 1, 5, and 10minutes of life, respectively. The birth weight, length,and OFC were greater than 95%, greater than 95%, and75%, respectively. The infant required intubation inthe delivery room and jet ventilatory support in theneonatal intensive care unit. He developed bilateralpneumothoraces, which necessitated the placement oftwo chest tubes. At approximately 6 hours of life, theinfant was noted to have decreasing oxygen satura-tions. A cardiac murmur was noted and an echocardio-gram demonstrated double-outlet right ventricle, a ma-laligned VSD, pulmonary atresia, right-sided aorticarch, and a left-sided, turtuous ductus arteriosus (Figs.1, 2). After the initiation of therapy with prosta-glandin E1, the oxygen saturations increased from 70to 85%.

In addition to his cardiac and respiratory problems,the infant was noted to be hypotonic and to have un-descended testes bilaterally, a small penis, and a blu-ish discoloration in the midline below a low-lying um-bilical stump. A modified Blalock-Taussig shunt wasperformed on day 2 of life. Postoperatively, the proposi-tus developed a urinary tract infection, and a urologicconsultation was obtained. An abdominal sonogram re-vealed ‘‘closed’’ bladder exstrophy and a double collect-

*Correspondence to: Zev Jacobson, M.D., Department of Pedi-atrics, Montefiore Medical Center, Centennial One, 111 East210th Street, Bronx, NY 10467. E-mail: zevjake@idt.net

Received 19 August 1997; Accepted 9 March 1998

American Journal of Medical Genetics 78:294–299 (1998)

© 1998 Wiley-Liss, Inc.

ing system bilaterally (Fig. 3). A vesiculoureterogramshowed moderate to severe vesicoureteral reflux.

On day 14 of life, the propositus underwent surgicalrepair of his bladder exstrophy. Also, surgical explora-tion of his peritoneum revealed bilateral testicular ves-sels, which both disappeared through the internal ringof the inguinal canals. No further exploration wasneeded.

While in the hospital, after the urologic surgery, thepropositus was noted to have a very poor suck withprojectile vomiting. He was fed entirely via a nasogas-tric tube. A gastrointestinal (GI) evaluation, includingan upper GI series and a pH probe, demonstrated se-vere gastroesophageal reflux. He was begun oncisapride with complete resolution of feeding problems.

Fig. 2. Echocardiogram (parasternal short axis view) showing pulmo-nary atresia; AO, aorta.

Fig. 4. Full face photograph of patient illustrating hypertelorism andflat nasal bridge with anteversion of nares.

Fig. 1. Echocardiogram (subxyphoid view) demonstrating double-outletright ventricle, malaligned VSD, and right-sided aortic arch. RAA, rightaortic arch; AV, aortic valve; RV, right ventricle; LV, left ventricle.

Fig. 3. Photograph of patient’s lower torso after his closed bladder ex-strophy repair.

Opitz G/BBB Syndrome 295

Because of the multiple anomalies, a genetics consul-tation was obtained. Growth parameters showedweight and length at 50% and OFC at 25% at 4 monthsof age. On examination, the propositus was noted tohave ocular hyperterlorism; his inner canthal and in-terpupulliary distances both exceeded the 95% percen-tile for age (32 and 52 mm, respectively). He also had aflat nasal bridge with anteversion of the nares and low-set, posteriorly rotated ears (Figs. 4, 5). In light of thesefindings, in addition to the urologic anomalies, feedingproblems, and congenital heart disease, a diagnosis ofOS was made. Karyotype revealed a 46,XY chromo-some complement. Using single-strand conformationalpolymorphism analysis, the propositus’ DNA wastested for the MID1 gene for OS in Xp22.3 by Dr. MaxMuenke at Children’s Hospital of Philadelphia, whodid not identify an alteration.

At 1 1/2 years of age, the patient underwent a Ras-telli repair for his heart disease and has done well post-operatively. His severe oropharyngeal dysphagia hasresolved with suck and swallow therapy, and his car-diac status has improved with digoxin therapy. Addi-tionally, the patient receives occupational and physicaltherapy. He began walking at 22 months, and at 24months was able to say 4 to 5 words. At that point,developmentally, he was felt to be functioning at an 11-to 12-month level. Of note, on physical examination,

Fig. 5. Side view of head illustrating low-set, posteriorly rotated ears.

TABLE I. Congenital Cardiovascular Defects in Patients With Opitz G/BBB Syndrome*

Literature cases

Cardiovascular defect

PDA ASD VSD Other/comment

Confirmed CHDCascos [1972] Case C2 + Primum type ASDCordero and Holmes [1978] Case 1 + +

Case 2 +Cote et al. [1981] Case 1 + Slight biventricular hypertrophyDe Silva [1983] Case 2 +Farndon and Donnai [1983] Case 1 Coarctation of aorta, aortic stenosis, pulmonic stenosisGilbert et al. [1972] Case 1 Absent coronary sinus, left cardinal vein entering the

IVC above the diaphragm and receiving the venousdrainage from the left side of the heart via the vein ofMarshall

MacDonald et al. [1993] Case 1 Right innonimate vein with absent right superior venacava and left superior vena cava draining into thecoronary sinus

Case 3 + + + Interrupted aortic archCase 4 + + + Coarctation of the aorta, single umbilical artery

Noe et al. [1984] 4 patients Cardiac anomalies (unspecified)Opitz et al. [1969b] Case 4 Coarctation of aorta with hypoplastic aortic archOpitz et al. [1969a] Case 4 + Patent foramen ovaleSchrander et al. [1995] Case 2 Tetralogy of FallotStevens and Wilroy [1988] Case 1 Coarctation of the aorta

Case 2 +Case 3 Pulmonary valve insufficiency

Stoll et al. [1985] Case 1 + + Pulmonic stenosisWilson and Oliver [1988] Case 2 Tetralogy of Fallot with severe pulmonic stenosis,

hypoplastic pulmonary arteries, and right sided aorticarch

Case 3 +Verloes et al. [1989] Case 1 Brachiocephalic trunk compressing the tracheaVerloes et al. [1995] II-10 Tetralogy of FallotPresent case + Double-outlet right ventricle, pulmonary atresia,

right-sided aortic arch, left-sided, tortuous ductusarteriosus

*ASD, atrial septal defect.

296 Jacobson et al.

TABLE II. Genitourinary System Malformations Other than Hypospadias Seen in Patients With Opitz G/BBB Syndrome

Literature cases

Genitourinary defect

Cryptorchidism Micropenis Other/comment

Cappa et al. [1987] Case 1 + Right testis on right kidney, left inguinal testisCase 2 +

Cavallo et al. [1988] Case 1 +Case 2 +

Christodolou et al. [1990] Case 1 + Anocutaneous fistula at the base of the penisCote et al. [1981] Family I,

Case 1+ Small meatus displaced to the left of the

midlineFamily II,

Case 1+ Small urinary meatus and phimosis

Cordero and Holmes [1978] Case 2 +Case 3 Right-sided hydrocele

Da Silva [1983] Case 1 + Cleft glans, hypoplastic and cleft scrotum,rectovesical fistula

Case 2 Cleft glansFarndon and Donnai [1983] Case 2 Two urethral openingsFryns et al. [1992] Case 1 + + Hypoplastic scrotum with prominent median

raphe, short perineumFunderburk and Stewart [1978] Case 2 Second urethral meatusGonzalez et al [1977] Case 1 + + Partially cleft scrotum, palpable right testicle

in the inguinal areaGreenburg and Schraufnagel

[1979]Case 1 +

Guion-Almeida andRichieri-Costa [1992]

Case 1 + + Rectoscrotal fistula, bifid scrotum

Case 2 + Hypoplastic scrotumCase 12 Vesicoureteral reflux (VUR)

Hogdall et al. [1989] Case III-2 + Rectourethral fistula, torsed and infarcted righttestis

Case III-6 Ambiguous genitalia, solitary testis adherent toposterior abdominal wall

Case IV-2(twin B)

Phimosis

Kasner et al. [1974] Case 1 Bifid renal pelvis with double ureterMacDonald et al. [1993] Case 1 Hypoplastic labia majora with anteriorly

displaced anusCase 3 +

Michaelis and Mortier [1972] Case 1 + Narrow urethral orificeNoe et al. [1984] 6 patients + Abnormal intravntricular pressures

(unspecified)Opitz et al. [1969b] Case 3 + Hypoplastic scrotum

Case 4 + Hypoplastic scrotumCase 6 +

Opitz et al. [1969a] Case 2 Bifid scrotum, rectourethral fistulaCase 3 Bifid scrotum, urethral meatus not patent

Pederson et al. [1976] Case 1 + Testes in the inguinal canalSchrander et al. [1995] Case 1 + Bifid scrotum, rectovesical fistula, bilateral

grade III VUR with hydronephrosisCase 2 Rectourethral fistula

Stevens and Wilroy [1988] 2 patients Bifid, medially displaced ureters1 patient Duplication of the calyceal system1 patient Duplication of the ureter with reflux

Stoll et al. [1985] Case 1 + + Cleft glans, hypoplastic scrotum, unpalpableleft testis

Urioste et al. [1995] Case 1 + Cleft scrotum with anterior displacement,ureteral reflux with anomalous vesicalimplantation of the ureter

Van Biervliet et al. [1975] Case 2 +Verloes et al. [1989] Case 2 + Rectourethral fistula

Case 3 + Bifid scrotum with ectopic but palpable testesVerloes et al. [1995] Case II-6 Rectoperineal fistula, imperforate hymen

Case II-8 Bilateral hydronephrosisCase II-10 Imperforate hymen with hematocolposCase III-6 VUR grade IIICase III-8 Bifid scrotum

Wilson and Oliver [1988] Case 2 + + Ambiguous genitalia, horseshoe kidney,bilateral rudimentary intra-abdominal testes

Young et al. [1988] Case 2 + Bifid scrotum, testes in inguinal canalPresent case + + Closed bladder exstrophy, double collecting

system, moderate to severe VUR

Opitz G/BBB Syndrome 297

both parents were noted to have normal facial appear-ances. Inner canthal (34 mm in father, 32 mm inmother) and interpupillary (60 mm in father, 58 mm inmother) distances were within normal range.

DISCUSSION

OS was initially described in 1969 as two separateentities, the G syndrome and the BBB syndrome. Thecollective title, Opitz G/BBB syndrome, emerged afterit became apparent that at least clinically, the G andBBB syndromes were a single disorder. However, re-cent molecular genetic mapping studies have demon-strated that OS is, in fact, a heterogenous disorder,with loci at 22q11.2 and Xp22 [Robin et al., 1995].Clinical features of families with OS linked to Xp22and 22q have recently been reviewed by Robin and co-workers [1996]. They concluded that no specific, defini-tive phenotypic findings could be assigned to the auto-somal or the X-linked genotypes of OS.

Half of the families (25 patients) studied by Robin etal. [1996] were linked to markers mapping to 22q11.2,the region that is deleted in the velocardiofacial syn-drome (VCFS), DiGeorge anomaly (DA), and conotrun-cal-anomaly face syndrome [Driscoll et al., 1992a,b;Burn et al., 1993]. Microdeletions of 22q11 have beenshown to contribute to the development of some cono-truncal cardiac malformations [Goldmuntz et al.,1993]. Only one of the 25 OS cases linked to 22q [Robinet al., 1995] had a congenital heart defect.

There is some overlap of the variety of congenitalheart disease seen in OS and DA/VCFS. In DA/VCFS,conotruncal defects are common. These include VSD,tetralogy of Fallot, interrupted aortic arch, coarctationof the aorta, vascular rings, right-sided aortic arch[Goldmuntz et al., 1993], and pulmonary stenosis [Lip-son et al., 1991; Seaver et al., 1994]. Similar heart de-fects have been described in OS. The spectrum of car-diac lesions seen in reported cases of Opitz syndrome isshown in Table I.

In their recent review of OS, Robin et al. [1996] statethat the most common heart defect seen in OS is patentductus arteriosus (PDA). This observation was basedon both a review of published cases and the authors’extensive unpublished experience (NH Robin, personalcommunication, 1997). Our review of the literature isin agreement with this observation. However, PDAmay be overrepresented. For example, in one report[Christodolou et al., 1990] of a patient with OS who hadring chromosome 22, the authors considered this pa-tient to have congenital heart disease by virtue of anechocardiogram done on day 2 of life which revealed asmall PDA. In approximately 20% of healthy infants,the ductus arteriosus remains patent until 96 hours oflife [Lim et al., 1992]. Patency of the ductus arteriosuson day 2 of life should not be considered pathological.Hence, we have not included this case among thosewith confirmed congenital heart disease (CHD).

Since its initial description, anomalies of the genito-urinary tract have been known to be cardinal featuresof OS. Summarized in Table II, abnormalities mostcommonly found in affected individuals include hypo-spadias, unilateral or bilateral cryptorchidism, bifid or

hypoplastic scrotum in males, splayed labia majora infemales, and various renal and ureteral anomalies inindividuals of both sexes. Although our patient did nothave hypospadias, he was found to have closed bladderexstrophy, an anomaly not previously reported in OS.

Closed exstrophy of the bladder, a rare variant of themore common open bladder exstrophy, is characterizedby a generalized muscular defect in the anterior ab-dominal wall, but no defect in the epidermal covering.In closed exstrophy, the bladder is bifid. Embryologi-cally, the defect results from failure of mesenchymalcells to migrate between the surface ectoderm and theurogenital sinus during the 4th week [Moore, 1993].

As previously noted, Robin et al. [1995] presentedevidence that Opitz syndrome is genetically heteroge-neous, with both X-linked and autosomal dominantlyinherited forms. Although attempts to identify a mu-tation at either of the loci reported by that group havenot yet been successful, the presence of anteversion ofthe nares, a ‘‘soft and subtle’’ finding reported by Robinet al. [1996] to occur only in the X-linked form of thedisorder, suggests that our patient has a mutation atXp22.

The finding of complex congenital heart disease andan apparently unique genitourinary tract anomaly inthis patient with OS further advances the theory thatthis condition is caused by an early developmental fielddefect involving the midline. The presence of closedbladder exstrophy, a defect in the migration of mesen-chymal cells during the 4th week of embryologic devel-opment, may provide an additional clue to the patho-genesis of this condition.

ACKNOWLEDGMENTS

We thank Drs. Maximilian Muenke and NathanielRobin for their assistance.

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