American Journal of Medical Genetics 31:349-355 (1988)

Brief Clinical Report

Meckel Syndrome With Polysplenia: Case Report and Review of the Literature

S. Shen-Schwarz and H. Dave

Department of Pathology, Magee- Womens Hospital and University of Pittsburgh School of Medicine, Pennsylvania

A 19-week gestation female fetus had multiple anomalies suggesting Meckel syndrome with polysplenia. In over 200 reported cases of Meckel syndrome, only 2 similar cases are documented. Both were male infants, one with bilateral left- sidedness (polysplenia), the other with bilateral right-sidedness (M-anisosplenia). Meckel syndrome is a complex MCA (multiple congenital anomaly) syndrome. Thus, the finding of polysplenia is to be interpreted as another such midline anomaly, rather than as a causally independent malformation.

Key words: polysplenia syndrome, midline developmental field, body symmetry, laterality

INTRODUCTION

Meckel syndrome is a rare autosomal recessive disorder. Common manifesta- tions include occipital encephalocele, post-axial polydactyly, cleft lip and palate, cystic dysplastic kidneys, and liver with portal fibrosis and bile ductular proliferation [Salonen, 19841. Polysplenia is a developmental field defect of altered laterality [Mathias et al., 19871, involving situs anomalies, complex cardiac defects, and splenic anomalies wan Mierop et al., 19721. Most cases of polysplenia are sporadic; how- ever, familial clustering has been reported [Arnold et al., 1983; Mathias et al., 19871. We report on a 19-week gestation female fetus with apparent Meckel syndrome with polysplenia. Such an association has been reported only twice previously.

CLINICAL REPORT

A 19-week gestation female fetus was born to a 25-year-old gravida 4, para 3 white mother with uneventful antenatal course. On routine ultrasound examination, occipital encephalocele and enlarged kidneys were noted. Amniotic fluid examination

Received for publication January 9, 1988; revision received May 2, 1988.

Address reprint requests to Dr. S. Shen-Schwarz, Department of Pathology, Children’s Memorial Hospital, Chicago, IL 60614.

0 1988 Alan R. Liss, Inc.

350 Shen-Schwarz and Dave

showed markedly elevated AFP level and the presence of acetylcholinesterase. Chro- mosomes were normal (46,XX).

The father, a 27-year-old white man, is in good health, and the mother smokes. The parents are not consanguineous, and there is no history of exposure to harmful chemicals or physical agents. The parents have been married for 10 years and have 3 daughters, ages 8, 7, and 2 years. Mother’s sister and grandmother have epilepsy, a maternal first cousin has a repaired ventricular septal defect, and a paternal first cousin has dextrocardia.

The 150g female fetus was macerated due to saline termination of pregnancy. Size was consistent with 17 weeks of gestation: crown-rump length 13 cm, crown- heel length 18.5 cm, and foot length 2 cm.

The head was small (head circumference 12 cm, biparietal diameter 3.5 cm). A 3 x 1 x 1 cm encephalocele protruded from a defect in the posterior fontanelle. The face was abnormal in appearance with sloping forehead, microphthalmia, hypotelor- ism, pointed tip of nose, and apparently low-set ears. The palate was highly arched with a v-shaped posterior cleft, involving both hard and soft palate. The neck was short and webbed. The chest was small. The abdomen was distended. The umbilical cord had 2 blood vessels. The spine was intact without neural tube defect. The external genitalia were normal. There was postaxial polydactyly of hands and feet, syndactyly of the fifth toe, and the extra digit on the right foot.

The immature fetal brain weighed 12 g; detailed examination was impossible because of the autolysis. Both cerebral hemispheres were abnormal in shape with absent olfactory bulbs. The occipital encephalocele was covered by meninges but not skin. Tectum was absent over the midbrain and pons. The cerebellum was small and abnormal in shape.

The heart was located in the midline, with apex pointing towards the right. There were 2 morphologically left atria; a persistent left superior vena cava drained into the atrium on the left. The left pulmonary veins drained into the atrium on the left. In a symmetrical manner, close to the midline, the right pulmonary veins drained into the atrium on the right. There was a large atrial septum primum defect continuous with a ventricular septal defect (persistent common atrioventricular canal). The right ventricle and pulmonary artery were hypoplastic, and the pulmonic valves were stenotic. The aorta and main pulmonary artery were in their normal relationship. The aortic arch was right-sided, the right subclavian artery arose from the descending aorta. The main pulmonary artery divided into the left pulmonary artery and ductus arteriosus, from which the right pulmonary artery arose. Due to autolysis of the liver, evaluation of the inferior vena cava, hepatic, or portal veins was not possible. The right umbilical artery was absent.

Both lungs were hypoplastic and morphologically left with 2 lobes on each side and hyparterial major bronchi.

The liver was symmetric with relatively larger left lobe. Gallbladder was present in the midline. The stomach was located on the left. One large multilobate spleen and 9 small splenic nodules were present in the left mesogastrium. The intestine was rotated but not fixed; cecum and appendix were located in the right upper quadrant. The diaphragm was intact. Microscopically, the liver showed periportal fibrosis and bile ductular proliferation.

Both kidneys were markedly enlarged and histologically showed cystic dysplas- tic changes. The ureters and bladder were hypoplastic.

Meckel Syndrome With Polysplenia 351

The placenta weighed 118 g. No gross abnormalities were observed except for the 2 vessels in the umbilical cord. Microscopic examination documented villous dysmaturity, trophoblastic inclusions, and stromal hypercellularity .

DISCUSSION

Meckel syndrome was first described in 1822 by Meckel [Meckel, 18221; in 1934, Gruber named it “dysencephalia splanchnocystica” [Opitz and Howe, 19691. Over 200 cases have been reported [Casamassima et al., 19871; however, diagnostic criteria are still not well-defined [Fraser and Lytwyn, 1981; Anderson, 1982; Salonen, 1984; Casamassima et al., 19871. It is generally accepted that at least 2 of the 3 main manifestations, namely, occipital encephalocele, polycystic kidneys, and polydactyly should be present to establish the diagnosis. Others [Hsia et al., 19711 stated that the minimal criteria should be 2 of above plus additional anomalies such as cleft lip and palate, microcephaly, central nervous system malformations, facial characteristics, hepatic abnormalities, and others as listed in Table I. Since many of these anomalies are nonspecific and may be seen in other malformation syndromes, Salonen [1984] proposed that the following 3 be considered minimal criteria for the diagnosis of Meckel syndrome: cystic dysplasia of the kidneys, periportal fibrosis with bile ductular proliferation and cystic dilation in the liver and occipital encephalocele or some other brain malformation. The case described in this report fulfilled this definition, but has additional cardiac, pulmonary, and splenic malformations that are unusual in Meckel syndrome.

Complex cardiac malformations are rare in Meckel syndrome [Opitz and Howe, 1969; Fraser and Lytwyn, 1981; Anderson, 1982; Salonen, 19841. The anomalies usually include atrial septal defect of the secundum type, ventricular septal defect, patent ductus arteriosus, single umbilical artery, and hypoplastic left heart syndrome. Accessory spleens may be present in 11 % to 22% of reported cases of Meckel syndrome [Anderson, 1982; Salonen, 19841; however, asplenia and polysplenia are infrequent. Lobation of the lungs is rare; one case of bilateral bilobed lungs was mentioned without description of the bronchial configuration [Hsia et al., 197 11.

In the case reported here, the constellation of multiple spleens, bilateral mor- phologic left lungs, bilateral superior vena cava, morphologic left atria with symme- tric pulmonary venous return, common atrioventricular canal, right-sided cardiac apex and prominent left lobe of the liver are diagnostic of the polysplenia complex [Van Mierop et al., 1972; Landing, 19841. However, in this syndrome, cystic dysplastic kidneys, hepatic abnormalities, and central nervous system anomalies have not been reported [Moller et al., 1967; Rose et al., 1975; Peoples et al., 19831.

Table I lists the anomalies present in our patient and cites the occurrence of such anomalies in the Meckel syndrome and in polysplenia patients as described in large series of these conditions [Opitz and Howe, 1969; Hsia et al., 1971; Fraser and Lytwyn, 1981; Anderson, 1982; Salonen, 1984; Casamassima et al., 1987; Moller et al., 1967; Van Mierop et al., 1972; Rose et al., 1975; Peoples et al., 1983; Landing, 19841. It appears therefore, that our patient has the Meckel syndrome and a distur- bance in the development of sidedness of the body. A review of the recent English literature covering about 200 cases of Meckel syndrome and 200 cases of polysplenia, we found 2 cases of Meckel syndrome with polysplenia [Hsia et al., 1971; Moerman et al., 19821 and one case with absent spleen [Salonen, 19841.

352 Shen-Schwarz and Dave

TABLE I. Anomalies Observed in our Case and Their Occurrence in Meckel Syndrome and Polysplenia Cases*

Anomalies present in Meckel syndrome polysplenia cases Frequency in Frequency in

this case (%) (96)

External Occipital encephalocele Microcephaly Cleft palate Ear anomalies Nose anomalies Webbed neck Small chest Polydactyly , postaxial

Cardiovascular Bilateral SVC Common AV canal Pulmonic stenosis Right sided aortic arch Anomalous PV return Distal origin of RSA Single umbilical artery

80-90 44 - 63 30 - 56 19 - 36 9 30 - 56 + 76 - 92 10 - 41

Rare Rare Rare Rare

t

95-100 41 48 33 44 39

5 -

Others Bilateral left lungs Rare 58-75

- Hypoplasia, lungs 30 Cystic dysplastic 81-100 -

kidneys Liver abnormalities 50-100 -

Accessory spleens 1 1-22 NA (By definition) Poly splenia Rare 100 (By definition)

*SVC = superior vena cava; AV = atrio-venticular; PV = pulmonary venous; RSA = right subclavian artery; NA = not applicable; + = present; - = missing data.

The first case described by Hsia et al. [1971], was one of a set of male MZ twins born at 34 weeks of gestation (Table II). The infant had renal and hepatic abnormalities, cleft lip and palate and other anomalies, but no central nervous system malformations. The cardiac malformation consisted of a bilateral superior vena cava, common atrium and what appeared to be persistent common atrioventricular canal; aortic and pulmonary outflow tracts were not described. Multiple spleens were present beneath the right hemidiaphragm. Although pulmonary isomerism was not described, this infant appeared to have the polysplenia developmental field defect.

The second case reported by Moerman et al. [1982] was a term male (Table 11) with occipital meningomyelocele, polydactyly, cystic dysplastic kidneys and hepatic abnormalities, absent olfactory bulbs and tracts, hypoplastic optic nerves and chiasma, hypoplastic cerebellum, partial agenesis of corpus callosum, and abnormal right lateral ventricles and basal ganglia. This infant had right isomerism of lungs, situs inversus involving the atria but not the ventricles, a bilateral superior vena cava, total

Meckel Syndrome With Polysplenia 353

TABLE 11. Anomalies Observed in the 3 Cases of Meckel Syndrome With Polysplenia*

Anomalies Patient Hsia et al. Moerman

et al.

External: Brain malformation Occipital encephalocele Sloping forehead Cleft palate Nose abnormality Ear, apparently low-set Small chest Pol ydacty I y

Cardiovascular: Bilateral SVC

Atria Ventricles

Apex

Common AV canal Pulmonary stenosis Right aortic arch Pulmonary venous return

Umbilical Artery Others:

Sex Lungs Cystic dysplastic kidneys Liver with portal fibrosis

+ To right Both left Hypoplastic

right + + + 2 Veins in

each atrium

Absent right

Female Both left + +

+ + ND

-

-

+ To right Common single Single

+ ND ND 4 Veins in

common atrium

ND

Male ND + +

and larger lobe, left Spleen 1 Larger; 9 5 Small spleens

+ To left Situs inversus Double outlet

+ + + 4 Veins in

right

right atrium

ND

Male Both right + + 1 Large, 2

smaller: left on right Y small right

*+ = present; - = absent; ND = not described; SVC = superior vena caval; AV = Atrio-Ventricular.

anomalous pulmonary venous return to the atrium on the right, persistent common atrioventricular canal, double outlet right ventricle, infundibular pulmonary stenosis , right aortic arch and one large lobated and 2 small spleens (anisosplenia) on the right side. This combination of malformations constitutes a condition of bilateral right- sidedness, or “M-anisosplenia” [Landing, 19841.

The case listed as number 24 in the Meckel syndrome series of Salonen [1984] was a female with additional findings of asplenia and unspecified heart defects. The disturbance in sidedness was not mentioned, and there is insufficient information to include this case into our analysis. However, from the discussions to follow, it is not unreasonable to assume tht asplenia may be an uncommon manifestation of Meckel syndrome.

The case presented here is the third case of Meckel syndrome with multiple spleens and is the fourth case in which Meckel syndrome is associated with distur- bances of body symmetry and/or anomalies of spleen development.

354 Shen-Schwarz and Dave

One of the characteristics of human internal body configuration is lateral asymmetry, or “sidedness.” In anomalies of the spleen, one observes a marked tendency for symmetric development of normally asymmetric organs. Bilateral right- sidedness is seen in asplenia or M-anisosplenia, while bilateral left-sidedness is seen in polysplenia or F-anisospleni [Landing, 19841. Most of these occurrences are sporadic, but autosomal recessive inheritance has been reported in polysplenia [Ar- nold et al., 1983; de la Monte and Hutchins, 19851. More importantly, recent asplenia and polysplenia have been reported in different individuals of the same family [Zlotogora and Elian, 1981; Niikawa et al., 1983; Mathia et al., 19871. Thus, there is evidence for a common causation of both conditions and for the conclusion that asplenia and polysplenia may be different manifestations of a single defect in the development of sidedness or laterality of the body.

The association of altered laterality of the body in Meckel syndrome, in our opinion, should not be regarded as a fortuitous event. Meckel syndrome with its neural tube closure defect, brain malformations, and median clefting of the lip and palate was noted by Opitz and Gilbert [1982] to consist in part of severe midline developmental field defects. The same authors stated that the midline is the plane around which symmetry (or asymmetry) of visceral organs is determined. In the 3 cases of Meckel syndrome with polysplenia, there is sufficient evidence to suggest that the Meckel syndrome consists in part of multiple midline anomalies, one of which includes determination of sidedness, in this case the polyasplenic field defect. Thus, the Meckel syndrome gene emerges as another of several mutations known to affect the development of body (a)symmetry, supporting again the hypothesis of causal heterogeneity of all developmental fields.

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