American Journal of Medical Genetics 101:328±333 (2001)

Organ Asymmetries as Correlates of Other Anomalies

Mason Barr, Jr.*Departments of Pediatrics, Pathology, and Obstetrics, University of Michigan, Ann Arbor, Michigan

Fetuses with deviations in the normal leftversus right weight relationships of thepaired viscera were examined for correla-tion with particular malformations, syn-dromes, or other common factors.Alterations of the normal pattern wereobserved among cases with cytogeneticanomalies, diaphragmatic hernia, renalduplication, dyshydramnios, and singleumbilical artery. A reversal of the left versusright weight pattern was found in theadrenals of cases with hepatic situs inversusbut not in those with heterotaxic cardiaclesions. Recipient twins in the twin±twintransfusion syndrome had reduced left lungweights, presumably because of inhibitionof lung growth by the enlarged heart. Theside of umbilical artery absence did notpredict either the nature or complexity ofassociated malformations. However, it issuggestive that there is discordance bet-ween the side of the missing artery andunilateral renal abnormality and that thereis preferential absence of the right or leftartery, depending on the karyotype.ß 2001 Wiley-Liss, Inc.

KEY WORDS: adrenals; kidneys; lungs;umbilical arteries; asym-metry; anomalies

Humans, as all vertebrates, are classi®ed as bilat-erally symmetrical animals. However, it is commonlyrecognized that considerable asymmetry exists in thenormal individual. There is obvious asymmetry in theheart, lungs, and liver and in the position of theabdominal viscera. Several of the viscera are paired butnormally show a measure of weight asymmetry. Theseinclude the lungs, kidneys, adrenals, and gonads. Inthis article, consideration will be given to deviationsfrom the usual left±right weight relationship of the

paired viscera (except the gonads) and their correlationwith certain anomalies or disorders. This study will notaddress the question of total organ weight deviation,only the deviation from the normal difference of weightbetween organs of opposite position. Attention will alsobe given to the morphologic associations of singleumbilical artery, depending on the side of arterialabsence.

MATERIALS AND METHODS

The study group for this investigation was drawnfrom the University of Michigan Teratology Unit dataset, a series of 4,347 fetal autopsies performed inconsistent fashion by one prosector. Cases with morethan minimal maceration, death more than 12 hoursafter delivery, body weight less than 50 g, or priorformalin ®xation were excluded. Not all cases hadcomplete sets of weights of the organs under considera-tion. Among the 2,062 cases for analysis, there were2,033 for adrenals, 1,954 for kidneys, and 2,024 forlungs.

The methodology of collecting fetal visceral weightdata and calculating normal growth curves for humanfetuses has been published [Barr et al., 1994]. Usingonly normal fetuses, growth curves were computed forleft versus right organ for each of the paired viscera:adrenals, kidneys, and lungs (Fig. 1). Although thecombined (i.e., left plus right) weight of these organsplotted against body weight is best described by powerequations with polynomial exponents [Barr et al.,1994], the relation of left versus right organ isadequately described in each case by a linear equation,indicating no preferential acceleration or decelerationof growth on either side. From the regressions and theirstandard deviations, z-scores for left versus right werecalculated for each set of paired viscera in the studygroup. The formulae used, with organ weights ingrams, were

zLvR adrenal : ðL adrenal ÿ ðÿ0:01522

þ ð1:14133 � R adrenalÞÞÞ=ð0:08953 � R adrenalÞ

zLvR kidney: ðL kidney ÿ ð0:00228

þ ð1:02150 � R kidneyÞÞÞ = ð0:07566 � R kidneyÞ

zLvR lung : ðL lung ÿ ð0:09009

þ ð0:79678 � R lungÞÞÞ = ð0:04315 � R lungÞ:

*Correspondence to: Mason Barr, Jr., M.D., Pediatric Genetics-Teratology, 1924 Taubman Center, Box 0318, University ofMichigan Hospitals, Ann Arbor, MI 48109.E-mail: barr@med.umich.edu

Received 8 November 2000; Accepted 1 December 2000

ß 2001 Wiley-Liss, Inc.

Thus, on average the right adrenal accounts for 47% oftotal adrenal weight, the right kidney for 49.5% of totalrenal weight, and the right lung for 56% of total lungweight. This type of analysis does not inform about total

organ weight, nor does it necessarily distinguishbetween one side being too heavy and the opposite sidebeing too light. However, from prior studies thatdistinction can often be made [Barr, 1994, 1997, 1998].

When the total population studied (2,062) wasdivided into morphologically normal (920) or abnormal(1,142) fetuses, the distributions of left versus rightorgan z-scores for the normal fetuses formed theexpected normal bell-shaped ®gures. However, in thecase of the abnormal fetuses, the ends of the curveswere considerably extended, re¯ecting the presence ofmany aberrations. The reports of cases with z-scoresoutside the 95% prediction interval were screened formalformations, diagnoses, and other common factors. Ifa particular factor appeared to occur with unusualfrequency, the distribution of z-scores for all cases withthat factor was examined in more detail. Manydiagnoses in the study group were represented by toofew cases to perform a meaningful analysis of z-scoredistribution.

RESULTS

Paired Viscera

Among fetuses with one of the common autosomaltrisomies, deviations from the usual left±right relation-ship were seen (Fig. 2). In trisomy 21 (108), there was ashift toward more equal weight of the adrenal glandsfrom the normal pattern of the left gland being theheavier. The left lung is normally lighter than the rightlung, but this difference between the two sides wasmore pronounced in fetuses with Down syndrome. Thelung z-score distributions were unaffected by thepresence or absence of major cardiac defects. Nodeviation from the usual pattern was found for thekidneys. In trisomy 18 (39), the predominant featureseen in the three organs was an excessive number ofoutliers, both high and low, when compared to thenormal left±right weight patterns, although there alsoappeared to be a trend to more equal adrenal weights.In trisomy 13 (35), there was a tendency for the leftkidney to be lighter (or the right, heavier), and the leftlung to be heavier (or the right, lighter). The adrenalsshowed the normal pattern. In fetuses with Turnersyndrome (35), no signi®cant deviations from theexpected left±right weight differential of the threeorgans were found (data not shown).

The distributions of z-scores of left versus right lungweight were examined for fetuses associated witholigohydramnios (311) or polyhydramnios (131). Inboth instances, there were excessive numbers of out-liers, both high and low, re¯ecting the wide variety ofstructural abnormalities associated with abnormalamniotic ¯uid volume (Table I).

In anencephaly (92), the adrenals showed an excessof instances in which the glands were more nearlyequal in weight than in normal fetuses (Table I).However, this may be misleading because the adrenalsin anencephaly are typically diminutive, and smallweight differences may be overinterpreted. For fetuseswith myeloschisis (70), there were no appreciable

Fig. 1. Scatterplots of weight of left versus right adrenal, kidney, andlung. Note the inequality of the adrenals and of the lungs that remainsconstant throughout gestation, whereas renal weights remain nearly equalto each other.

Organ Asymmetries 329

deviations from the usual weight patterns of the threeorgans studied (data not shown).

The distribution of z-scores of left versus right kidneyweight in instances of unilateral renal duplication wasexamined. As expected, the duplicated kidney washeavier, whether on the left (21) or the right (15) (Fig.3). It is possible that some cases of ``fused renalduplication'' were not recognized at autopsy andaccount for other cases in which the left±right weightsdeviated from the usual pattern of near equality.

In cases of diaphragmatic hernia (33 left, 10 right),the lung weights were most reduced on the side of theherniation, the exceptions being found in cases withvery complex malformation patterns or the presence of

pulmonary sequestration in the contralateral lung(Table I).

An interesting observation was made in casesaffected by the twin±twin transfusion syndrome. Therecipient twins (38) were found to have reduced weightof the left lung, an alteration not found in the donortwins (28) (Fig. 3). It has been previously reported thatone of the earliest manifestations of hemodynamicimbalance in the twin±twin transfusion syndrome iscardiac enlargement caused by myocardial hyperplasiain the recipient twin [Pridjian et al., 1991]. The ob-served lung weight discrepancy is likely a mechan-ical effect on the developing lung from the enlargedheart.

Fig. 2. Z-score distributions of left versus right adrenals, kidneys, and lungs for trisomies 21, 18, and 13. The shaded area is�2 SD (approximately the95% prediction interval). The black areas are those cases falling outside the 95% prediction interval. A heavy bar marks the central point (Z�0).

TABLE I. Left Versus Right Z-Score Distributions for Selected Conditions and Organs

Disorder Organ

Z-score

<ÿ1.95 ÿ1.95 to �1.95 >�1.95(2.5%) (95%) (2.5%)

Polyhydramnios Lungs 28 81 21Oligohydramnios Lungs 38 231 41Anencephaly Adrenals 7 55 27Diaphragm defect left Lungs 21 6 5Diaphragm defect right Lungs 1 0 9

330 Barr

Cases with situs ambiguity were examined. Whensitus inversus of the liver was used as the selectioncriterion (9), left-versus-right adrenal weights werefound to be reversed from the usual pattern (Fig. 3). Nosuch effect was found in cases with intestinal malrota-tion (73) (Fig. 3) or cardiac heterotaxy (44) (not shown).

Umbilical Arteries

Ordinarily, there are two umbilical arteries, but inapproximately 1% of births one of these vessels isabsent, either because only one developed or becauseone regressed. It is well known that single umbilicalartery is associated with an increased likelihood ofother anomalies, particularly of the genitourinary andcardiovascular systems. The entire University of

Michigan Teratology Unit data set (4,347) was sur-veyed for cases of single umbilical artery: in 112 the leftartery was absent, in 126 the right artery was absent.There were eight instances in which the vessel to theplacenta was of vitelline origin and eight in which theside of the vessel could not be determined (acardiacfetuses).

Abuhamad et al. [1994] reported a series of 60 casesof single umbilical artery in which absence of the leftartery was more commonly associated with anomalies,particularly multiple and cytogenetic anomalies. In mydata set, the mean number of different organs or bodyregions affected did not differ, depending on whichartery was absent (Table II). When grouped by systemswith malformations, there was only one statisticallysigni®cant correlation with the side of the arterial

Fig. 3. Z-score distributions of left versus right for kidneys in unilateral renal duplication, lungs in the twin±twin transfusion syndrome, and adrenalsin intestinal malrotation compared to hepatic situs inversus. The shaded area is � 2 SD (approximately the 95% prediction interval). The black areas arethose cases falling outside the 95% prediction interval. A heavy bar marks the central point (Z�0).

Organ Asymmetries 331

absence. Those fetuses with genital anomalies weremore likely to be missing the left artery (Table II). Infetuses that had both a single umbilical artery and acytogenetic anomaly, the missing artery appeared to bemore commonly on one side, but the side varied by thekaryotype (Table II).

The association between renal malformation andsingle umbilical artery (89) was examined in moredetail. When both kidneys were abnormal, the rightartery was absent in 21 cases and the left artery wasabsent in 33 cases. When only one kidney wasabnormal, there was discordance (23) more often thanconcordance (12) for the side of arterial absence,although this did not reach statistical signi®cance (P0.063) (Table III). The search for association of singleumbilical artery with deviation in the left±rightweights of the paired viscera showed a sizable numberof outliers, both high and low, re¯ecting the severity ofthe associated malformations, with perhaps an excessof high lung outliers (i.e., left lung heavier or right lunglighter than usual) associated with absent left umbili-cal artery (data not shown).

Blackburn and colleagues [1993a,b] reported thatabsence of an umbilical artery was associated with alonger foot length on the ipsilateral side. AlthoughBlackburn and I use different methods to measure foot

length, I would expect his reported mean difference infoot length of 2.5 mm to be apparent with mymethodology, but it was not. The vast majority of caseswith single umbilical artery showed no appreciabledifference (i.e., <1 mm) in foot length. Of 11 cases witha difference in foot length greater than 1 mm, 7 followedBlackburn's prediction, and 4 did not. This offers onlyweak support for a correlation between umbilical arteryabsence and accelerated extremity growth.

DISCUSSION

If in utero growth disturbance affected the left andright sides equally, the usual weight differentialbetween the left and right sides of the paired viscerawould be maintained. From the data presented in thisarticle, it can be seen that this is not always the case,and some of the deviations from proportionate growthappear to be correlated with particular malformationsor syndromes. The reason for this imbalance in growthis not always evident and merits further consideration.In some cases, such as restriction of lung growthaccompanying diaphragmatic hernia or cardiac enlar-gement, a simple mechanical effect on organ growthcan be surmised. It is inferred that the reason the leftlung normally weighs less than the right is that the left-positioned heart impedes left lung growth.

An increased weight of a unilaterally duplicatedkidney is to be expected. What is more puzzling is theincreased weight of a solitary kidney. Hartshorne et al.[1991] reported that in isolated unilateral renal agen-esis, the weight of the remaining kidney was increased,so that the renal weight approximated 80% of theanticipated weight of two kidneys. Some of the casesin that report were drawn from this data set. Whycompensatory overgrowth of the solitary kidney occursin utero when the fetus presumably depends largely onthe placenta for excretory function remains a mystery.

The reversal of the usual weight difference betweenthe adrenal glands in association with hepatic situsinversus may be interpreted as a direct manifestationof the left±right inversion process itself, or alterna-tively it may be consequent to inversion of the regionalvasculature. The fact is that we have no understandingof why the right adrenal normally weighs less than theleft.

In other instances, such as the greater equality ofadrenal weights and greater restriction of left lunggrowth in Down syndrome, the basis for the growthaberration is not apparent. Some of the disorders

TABLE II. Correlations of Single Umbilical Artery by Side ofMissing Artery

Number of systems withmalformation

Left arteryabsent

Right arteryabsent

None 16 111 14 132 12 133 16 174 19 145 13 156 5 57 1 128 12 89 5 3

10� 3 1Mean 4.01 3.89

System affected

Body wall* 28 20Central nervous 17 27Cardiovascular 66 63Diaphragm 13 8Gastrointestinal 50 49Genital** 60 40Urinary 52 52Axial skeletal 33 34Limb 30 29Respiratory 16 10Situs ambiguity 5 4

Cytogenetic anomaly

Trisomy 13* 11 5Trisomy 18 7 12Trisomy 21* 14 745,X* 14 7Triploidy** 1 9

*P< 0.10 (chi� square).**P<0.05 (chi� square).

TABLE III. Renal±arterial concordance

Kidney Umbilical artery Number

Both abnormal R absent 21Both abnormal L absent 33R abnormal R absent 6R abnormal L absent 12L abnormal L absent 6L abnormal R absent 11Concordant 12Discordant 23

332 Barr

examined here, notably trisomies 18 and 13, singleumbilical artery, and dyshydramnios, are character-ized by excesses of both high and low z-scores, re¯ectingthe complex and variable nature of the associatedmalformations. This is of some signi®cance becausefetuses with cytogenetic anomalies have been describedas showing ``symmetrical'' growth restriction [Reeceand Hagay, 1992], whereas a more detailed look at theirgrowth patterns shows a great deal of asymmetry[Barr, 1994].

Over the years, there have been many articlesdetailing the incidence and morphologic associationsof single umbilical artery (not cited here). Few studieshave looked at the correlation of side of involvementwith the type or laterality of associated malformations.Despite one report to the contrary [Abuhamad et al.,1994], there is no convincing evidence of correlationbetween the side of arterial absence and the nature orcomplexity of concomitant malformation. Two excep-tions to this are suggested. One is the apparentdiscordance between the side of the missing arteryand unilateral renal abnormality. The other is thepreferential absence of right or left artery depending onthe karyotype. Study of more cases should verify orrefute these observations.

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Barr M. 1994. Growth pro®les of human autosomal trisomies at midgesta-tion. Teratology 50:395±398.

Barr M. 1997. Growth as a manifestation of teratogenesis: lessons fromhuman fetal pathology. Reprod Toxicol 11:583±587.

Barr M. 1998. Correlates of prenatal visceromegaly. Am J Med Genet79:249±252.

Barr M, Blackburn WR, Cooley NR. 1994. Human fetal somatic and visceralmorphometrics. Teratology 49:487±496.

Blackburn WR, Cooley NR, Stevenson RE. 1993a. New perspectivesregarding umbilical cords containing a single artery. Proc GreenwoodGenetics Center 12:134.

Blackburn W, Cooley NR, Stevenson RE, Martin RA, Jones KL. 1993b.Studies supporting the concept of vascular steal and asymmetric lowerextremity growth in the human fetus. Proc Greenwood Genet Center12:44±46.

Hartshorne N, Shepard T, Barr M. 1991. Compensatory renal growthin human fetuses with unilateral renal agenesis. Teratology 44:7±10.

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