Heterotaxia in a Fetus With Campomelia, CervicalLymphocele, Polysplenia, and MulticysticDysplastic Kidneys: Expanding the Phenotype ofCumming Syndrome

Jeffrey E. Ming,1,2* Donna M. McDonald-McGinn,1,2 Richard I. Markowitz,3 Eduardo Ruchelli,4 andElaine H. Zackai1,2

1Division of Human Genetics and Molecular Biology, Children’s Hospital of Philadelphia and the University ofPennsylvania, Philadelphia, Pennsylvania

2Department of Pediatrics, Children’s Hospital of Philadelphia and the University of Pennsylvania,Philadelphia, Pennsylvania

3Department of Radiology, Children’s Hospital of Philadelphia and the University of Pennsylvania,Philadelphia, Pennsylvania

4Department of Pathology, Children’s Hospital of Philadelphia and the University of Pennsylvania,Philadelphia, Pennsylvania

We report on a fetus with tetramelic campo-melia, polysplenia, multicystic dysplastickidneys, and cervical lymphocele. This con-dition is similar to the autosomal recessivecondition described by Cumming et al.[1986: Am J Med Genet 25:783–790] and isdifferent from campomelic syndrome. In ad-dition, our case had anomalies not previ-ously described in this condition, includingabnormal lung lobation with bilateral leftbronchial morphology, dextrocardia, totalanomalous pulmonary venous return, a leftsuperior vena cava, and a right aortic arch.The pancreas was short, with absence of thebody and tail. These anomalies are similar tothose found in the polyasplenia spectrum. Wesuggest that the syndrome reported by Cum-ming et al. may be expanded to include poly-splenia with heterotaxia and that Cummingsyndrome may be considered another autoso-mal recessive condition associated with a lat-erality defect. Am. J. Med. Genet. 73:419–424,1997. © 1997 Wiley-Liss, Inc.

KEY WORDS: campomelia; polyasplenia;Cumming syndrome; hetero-taxia

INTRODUCTION

Campomelia, or ‘‘bent’’ limbs, is seen most frequentlyas part of campomelic syndrome. However, Cumminget al. [1986] reported on a case with campomelia, poly-cystic renal disease, cervical lymphocele, and polysple-nia. These additional anomalies distinguished it fromthe campomelic syndrome. Urioste et al. [1991] re-ported on two sisters with cystic kidneys and cervicallymphocele, one of whom had documented campomelia.In these three cases, there was no heterotaxia of thepulmonary or cardiovascular systems. We report on afetus with the syndrome described by Cumming et al.who had polysplenia, multicystic kidneys, cervical lym-phocele, campomelia, and laterality defects of theheart, lungs, and great vessels, findings not previouslyseen in the Cumming syndrome. Polysplenia and asple-nia are considered different manifestations of a com-mon set of morphogenetic errors. We suggest that het-erotaxia may be a component manifestation in thismalformation complex.

CLINICAL REPORT

The female fetus was the 23-week gestational ageproduct of a 25-year-old woman who had had one pre-vious miscarriage. The parents were nonconsanguine-ous. Prenatal ultrasound at 22 weeks showed echo-genic kidneys, ascites, shortening of the long boneswith campomelia of the femora and humeri, and oligo-hydramnios. A fetal dysrhythmia was present, with thefetal heart rate ranging between 60 and 130. A still-born female fetus was delivered at 23 weeks of gesta-tion. The fetus weighed 970 g (normal 408–640 g) andhad a length of 29.2 cm (normal 25.9–31.9 cm). Therewas hydrops, including massive ascites and small pleu-ral and pericardial effusions. The palpebral fissures

Contract grant sponsor: National Institutes of Health; Contractgrant number: HD07107.

*Correspondence to: Jeffrey E. Ming, Division of Human Ge-netics and Molecular Biology, Children’s Hospital of Philadel-phia, 34th and Civic Center Boulevard, Philadelphia, PA 19104.

Received 14 February 1997; Accepted 1 August 1997

American Journal of Medical Genetics 73:419–424 (1997)

© 1997 Wiley-Liss, Inc.

were upslanting, and the nose and pinnae were flat-tened (Fig. 1). There was redundant skin over the pos-terior aspect of the neck and upper back.

The lungs were severely hypoplastic and bilobed,with minimal development of interlobar fissures. Thebronchial morphology and bronchoarterial relationswere left on both sides.

The cardiovascular system had multiple anomalies(Fig. 2). Dextrocardia was present. Both atrial append-ages had a left morphology. There was leftward dis-placement of the septum primum with hypoplasia ofthe septum secundum. There was no venous connectionto the left atrium, as there was total anomalous pul-monary venous connection to an enlarged right atrium.The superior vena cava was left-sided and entered theright atrium directly. There was an azygos continua-tion of the inferior vena cava to the superior vena cava.There was no right superior vena cava. The left atrium,mitral valve, and left ventricle were hypoplastic. Aconoventricular septal defect was present. The aorticarch was on the right, with mirror-image branchingand a hypoplastic arch. Bilateral ductus arteriosi werepresent.

There were multiple visceral malformations. The ab-

domen was distended by massive ascites. The stomachand liver were normally positioned. Except for anoma-lous looping of the duodenum, the gastrointestinaltract was normal, and there was no evidence of atresia.The head of the pancreas was present, but the body andtail were absent (Fig. 3). Neither liver nor pancreaswas cystic grossly or microscopically. Polysplenia waspresent (Fig. 4). The kidneys were enlarged, with dif-fuse multicystic dysplasia throughout the renal paren-chyma (Fig. 3). Microscopic examination showed bilat-eral, symmetric cystic changes. Cysts of variable sizewere present throughout the cortex and medulla, con-sistent with multicystic renal dysplasia. Dilated med-ullary tubules were surrounded by laminar arrange-ment of mesenchyme. The renal collecting system waspoorly developed, and the bladder was hypoplastic. Theexternal genitalia were normal female, and ovaries,Fallopian tubes, and uterus were present. The brainwas normal on both gross and microscopic examina-tion. The eyes were not examined.

Numerous skeletal abnormalities were present (Fig.5). A narrow, bell-shaped chest and short, flared ribswere noted. All four limbs were short. The tibiae andulnae had severe campomelia; and the femora, fibulae,humeri, and radii were mildly bowed. Additionalanomalies were bilateral talipes equinovarus and poorossification and ridging of the acetabulae. Fingers twothrough five were short and had only a single flexioncrease; and, radiographically, only two phalanges werepresent in those digits. The lower margins of the iliacbones were spike-like. The skull, scapulae, clavicles,and spine were normal radiographically. The sternumwas not ossified. Histology of the rib, vertebral bodies,and femur showed an abnormal growth plate with dis-organization of the zones of hypertrophy and provi-sional calcification. There was excessive periosteal newbone formation and active remodeling. The karyotypewas normal female, 46,XX. Parents were not availablefor karyotypes.

DISCUSSION

The fetus in this report presented with tetrameliccampomelia, cervical lymphocele, polysplenia, andmulticystic renal dysplasia. This syndrome was re-ported first by Cumming et al. [1986]. Other findingsshared by our case and Cumming’s case include hypo-plastic lungs, short thorax, and clubfoot (Table I). Inaddition, Cumming’s case had a cleft palate, cystic dis-ease of the pancreas and liver, atresia of the cecumwith a short small and large bowel, absent olfactorybulbs, cryptorchidism, and clubfoot. Urioste et al.[1991] reported on two sisters with cystic kidney dis-ease and cervical hygroma. Both had short limbs andsmall hands. One had campomelia, whereas the otherdid not have radiologic studies. These children did nothave polysplenia. One had an ovoid pancreas with poordelineation between the head, body, and tail. She alsohad a fibrotic liver, and the other had a fibrotic pan-creas and a cleft lip. None of these cases had hetero-taxia.

The parents of the Cumming et al. [1986] case wereconsanguineous and had had two previous stillbirths.

Fig. 1. Postmortem photograph of fetus. Note the generalized edema,cervical lymphocele (arrow), abdominal distention secondary to massiveascites, and short limbs.

420 Ming et al.

The parents of the siblings reported by Urioste et al.[1991] were not known to be consanguineous, but theyshared the same surname and at least one of the sib-lings’ grandparents on each side of the family was bornin the same small town. These reports make autosomalrecessive inheritance likely. The parents of the fetus inthis case are not known to be consanguineous. They didhave a previous miscarriage, and little informationabout that pregnancy is available.

Additional patients with some of the anomalies pres-ent in the fetus of this report have been described.These include two unrelated fetuses with cystic hy-groma and bowed and short femora and tibiae [Tricoireet al., 1993]. They also had hypoplastic fibulae, narrowiliac wings, and 11 pairs of ribs. One had hypoplastickidneys and bilateral thumb agenesis, and the otherhad clubfeet. The parents of the second fetus were sec-ond-degree relatives. Campomelia and cystic dysplastickidneys were reported in a fetus of consanguineousparents [Ades et al., 1994]. The fetus also had occipi-toschisis, cerebral malformation, ocular coloboma, la-ryngeal dysplasia, cleft palate, ambiguous genitalia,and polydactyly.

Campomelia, or bowing of the limbs, is most com-monly present in campomelic syndrome. Skeletalanomalies commonly seen in this condition includebowed femora and tibiae, hypoplastic scapulae, abnor-mally developed pelvic bones, short first metacarpal,and talipes equinovarus. Bowing of the limbs, espe-cially the radii or ulnae, is uncommon [Mansour et al.,1995]. Pretibial skin dimples, arrhinencephaly, cleftpalate, pulmonary hypoplasia, and vertebral and ribanomalies may also occur. To date, polyasplenia andlaterality defects have not been seen in campomelicsyndrome. There are reports of renal medullary or glo-merular cysts and hypoplastic cystic kidney in this syn-drome [Austin et al., 1980; Houston et al., 1983], but

Fig. 3. Abdominal cavity. Note the short pancreas (P), anomalous loop-ing of the duodenum (D), and multicystic dysplastic kidneys (K).

Fig. 2. Thoracic cavity. Dextrocardia and a left-sided superior vena cava (S) are present. There is pulmonary hypoplasia (P).

Heterotaxia in Cumming Syndrome 421

Fig. 5. Radiographs showing skeletal anomalies. There is severe campomelia of the tibiae and ulnae. Mild bowing of the femora, fibulae, humeri, andradii are also present. Note the small chest with short flared ribs. The lower margins of the iliac bones are spike-like. A: Frontal view. B: Lateral view.

Fig. 4. Polysplenia. Multiple spleens of different sizes (arrows) are seen on both sides of the greater curvature of the stomach.

multicystic dysplastic disease has not been clearlynoted. Congenital heart disease can occur but is almostnever complex or severe [Mansour et al., 1995]. Cam-pomelic dysplasia is due to mutations affecting theSOX9 gene [Wagner et al., 1994; Foster et al., 1994].DNA sequence analysis of the complete coding region ofthe SOX9 gene and its exon/intron boundaries was per-formed in our case, and no mutations were identified(Dr. G. Scherer, personal communication).

This fetus had heterotaxia, because the bronchialbranching pattern and cardiac atrial appendages hadleft-sided morphology bilaterally. Many of the cardio-vascular abnormalities present in this case are oftenseen in individuals with heterotaxia. Polysplenia andasplenia are both associated with laterality defects andcongenital heart disease. This association has beentermed the Ivemark syndrome. Polysplenia and asple-nia are most likely different forms of the same devel-opmental field defect, and the term ‘‘polyasplenia’’ isused to describe this field defect [Opitz, 1985]. Poly-splenia is associated with bilateral ‘‘left-sidedness,’’ inthat both bronchi have a left-sided morphology, andanomalous pulmonary venous return frequently oc-

curs. The inferior vena cava often connects to the azy-gos or hemiazygos system. Short pancreas has alsobeen reported in association with polysplenia [Hata-yama and Wells, 1984; Herman and Siegel, 1991].

Polyasplenia anomaly is heterogeneous. The poly-asplenia spectrum is associated with a defect in theearly embryonic determination of asymmetry. Theremay be an interruption of the normal morphogeneticprocess that leads to asymmetry, probably by disturb-ing the midline developmental field. The anomaly isnot a specific malformation syndrome but, instead, canbe associated with other malformations in a nonran-dom fashion. Polyasplenia may be due to monogenicconditions, teratogens, or multifactorial causes.

Polysplenia is typically sporadic, although there areseveral reports of affected siblings [Rose et al., 1975;Hallet et al., 1979; Kawagoe et al., 1980; Arnold et al.,1983; Hutchins et al., 1983; de la Monte and Hutchins,1985]. Autosomal recessive inheritance is suggested bythe presence of consanguinity in some of the familialcases of polyasplenia. Another form of heterotaxia andpolysplenia identified in a kindred with affected malesin at least three generations has been mapped to Xq24-q27 [Mathias et al., 1987; Casey et al., 1993]. Kindredswith heterotaxia consistent with autosomal dominantinheritance have also been reported [Alonso et al.,1995].

The syndrome described in this report with poly-asplenia, skeletal anomalies, and multicystic renaldysplasia has the distinguishing defect of campomelia.We report only the fourth individual with this unusualcondition and note for the first time the presence ofheterotaxia. In addition, there are a few reports of skel-etal dysplasia, cystic kidneys, polyasplenia, lateralitydefects, and skeletal abnormalities without campome-lia [Fraser et al., 1989; Brueton et al., 1990; Majewskiet al., 1996]. The association of skeletal malformationsand renal-hepatic-pancreatic cystic disease with thepolyasplenia complex of severe congenital heart dis-ease and laterality defects may reflect an underlyingcommon element in the development of these organsystems. It is possible that these conditions represent adevelopmental field defect with varying manifestationsand may be due to a defect in a gene with a blastoge-netic effect.

ACKNOWLEDGMENTS

We thank Dr. Gerd Scherer for mutation analysis ofthe SOX9 gene. This study was supported in part bytraining grant HD07107 from the National Institutesof Health.

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TABLE I. Comparison of Present Case With Previous Reportsof Cumming Syndrome*

Cumminget al. [1986]

Urioste et al.[1991] Present

caseSib 1 Sib 2

Sex M F F FGestational age

(weeks)27 Term 37 23

Birthweight (g) 2,610 3,530 ? 970Length (cm) 40 35 ? 29.2Karyotype 46,XY ND 46,XX 46,XXGeneralized edema + + + +Arrhinencephaly + − − −Ectopic thyroid tissue − + − −Cervical hygroma + + + +Cleft lip or palate + − + −Short/bell-shaped

chest+ + + +

Pulmonary hypoplasia + − − +Abnormal bronchial

morphology− − − +

Dextrocardia − − − +Congenital heart

disease− − − +

Polysplenia + − − +Short intestines + − − −Cystic pancreas

disease+ − + −

Small pancreas − + − +Polycystic liver

disease+ + − −

Cystic kidney disease + + + +Short limbs + + + +Campomelia + ? + +Short hands + + + +Absent phalanges ? + − +Cutaneous toe

syndactyly− + + −

Talipes equinovarus + − − +Vertebral

abnormalities+ − − −

*ND, not done; Sib, sibling; M, male; F, female.

Heterotaxia in Cumming Syndrome 423

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