the genain quadruplets

VOL. 14, NO. 4, 1988 The Genain Quadruplets 595

by Allan F. Mlrsky andOlive W. Qulnn

Abstract

The Genain quadruplets are aunique set of monozygous womenwho are concordant for schizo-phrenia but discordant for theseverity of their disorder. Theywere studied by David Rosenthaland colleagues at the NationalInstitute of Mental Health in thelate 1950's when they were in theirtwenties and again in 1981 whenthey were 51. They are faring aboutas well now as they ever have intheir adult lives. The results ofpsychological tests, some of whichwere repeated more than 20 yearsapart, are discussed, as are theeffects of medication on attentionand memory. The differentialresponse of the Genains to neu-roleptic drugs, as well as certainother findings in the 1981 study,leads to a different conclusionabout the discordant severity oftheir disorder from that reached in1963 by Rosenthal and Quinn.These observations emphasize thevalue of long-term followup stud-ies in genetically relatedindividuals, with repeated assess-ments of the same functions.

The purpose of this article is toreview the implications of the fol-lowup study conducted on theGenain quadruplets. The Genainsare a rare set of monozygotic femalequadruplets, concordant for schizo-phrenia but discordant for theseverity of the illness. As children,they were celebrities in the mid-western city of their birth andperformed songs and dances as agroup at numerous social and civicoccasions. They had virtually noclose friends aside from oneanother and were closely super-vised by their mother. Mrs. Genaincould not, however, protect her

daughters from what appear tohave been pathogenic ministrationsof Mr. Genain. Mr. Genain wasprone to suspicious rages, whichone friend described as "frenzied."He spied on his daughters con-stantly and insisted on participatingin the most intimate aspects of theirlives, even after they entered ado-lescencewhen he became moresexually demonstrative. "Heshouted, cursed, paced, sulked,lied, feigned illness and 'heardnoises' His stated 'reasons' . . .were completely tangled and inap-propriate, so that one could notrespond to them in any rationalway..." (Rosenthal 1963, p. 556).Moreover, available evidence fromfamily histories suggests that thegenetic contribution to schizo-phrenia was probably due to Mr.Genain as well.

Hospitalized at the NationalInstitute of Mental Health (NIMH)in the mid-1950's when they werein their twenties, the women werestudied intensively by a group ofmental health scientists, led byDavid Rosenthal, who later becameChief of the Laboratory of Psychol-ogy and Psychopathology. Each ofthe quadruplets was assigned atherapist; and extensive efforts weremade, both to treat them and todetermine the causes of the dif-ferential outcome of theirschizophrenic disorder. The nameGenain, a pseudonym, was selectedby Rosenthal; it is derived from theGreek for dreadful gene. The infor-mation collected was summarizedand integrated in The Gennin Quad-

Reprint requests should be sent toDr. A.F. Mirsky, Laboratory ofPsychology and Psychopathology,National Institute of Mental Health,Bldg. 10, Rm. 4C-110, 9000 RockvillePike, Bethesda, MD 20892.

by guest on January 28, 2011schizophreniabulletin.oxfordjournals.org

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596 SCHIZOPHRENIA BULLETIN

ruplets (Rosenthal 1963). Thewomen, whose first names werealso selected by Rosenthal for hisbook, are Nora, Iris, Myra, andHester (i.e., NIMH, in order ofbirth).' They were examined withvirtually all of the methods avail-able in the 1950's for studyingschizophrenia and psychologicaldeficit.

Before presenting the details ofthe followup examination, we firstrecapitulate some of the family his-tory data (from Rosenthal 1963),together with selected significantlife events (1930-55) of each of thequadruplets.

Early Family History

The Parents. Henry Genain, theyoungest of nine children born ofGerman farmer immigrants whocame to this country when he was3'k years old, was said to be a"good-natured little fellow" as achild. His mother was described asincreasingly reluctant to bear chil-dren and during her last twopregnancies wanted to kill herselfand her husband. She tried to abortHenry by overwork: "cleaning thestables and lifting heavy things. Sheflailed grain on the day he wasborn in the hope that the babywould die if born out in the field"(Rosenthal 1963, p. 23). In herteens, she had had a "nervousbreakdown"; and the reportedsymptoms of this illness were

'This scheme was suggested by theoutcome of a baby-naming contest spon-sored by their hometown newspaperwhen the quadruplets were born. Theinitials of the winning names, in orderof birth, were those of the full name ofthe hospital in which they were born.

thought by a caseworker at NIMHto sound like paranoid schizo-phrenia. Henry's father was anoccasional drinker; an older brother,14 years Henry's senior and nevermarried, "was a domineeringdrunkard who became irrationalwhen angry" (Rosenthal 1963,p. 23). He was killed by a train ashe slept in a drunken stupor onthe tracks.

As a child, Henry was shy andfearful, continually worried that hismother might die. He was a stut-terer. Advised, as a young man, togive up drinking, he did so for awhile, and his speech defectimproved. In his twenties, hebecame less good-natured. He wasfairly sociable with a group ofyoung men in their twenties whenhe was 34. These friends thoughthim slow in comprehension. Untilafter his marriage and the birth ofhis girls, he was an unskilledlaborer.

Gertrude Hood Genain was theeldest of eight surviving childrenborn to a father she described askind but domineering, who hadbeen an only child and haddeveloped a "spoiled personality."Her mother, kind and sweet,helped her children "all she could,"but with 11 pregnancies, had littletime to spend with her first-born.Gertrude was pressed at an earlyage into caring for her younger sib-lings, and she also did her share offarm work. Gertrude expressed noill-feeling toward her mother, butshe resented her father's "prefer-ence for boys and his belief that . . .they should get as much schoolingas possible, while girls .. . neededno more than an eighth-gradeeducation" (Rosenthal 1963, p. 26).

At age 14, Gertrude, tired ofbeing "like a hired girl for thewhole family" (Rosenthal 1963,p. 26), packed her clothes and fled

to her grandmother's home. After ashort time, determined to get abetter education, she moved to anearby town, supporting herselfwith various jobs while sheattended high school. She sought tobecome a registered nurse but failedthe academic workunable to passLatin and chemistry. She thenworked as a practical nurse for hergrandfather's physician.

Gertrude and Henry met whenhe was in the hospital for minorsurgery. She professed no interestin him: he was 11 years her senior,overzealous in courting ("he gaveme so much attention that heannoyed me" [Rosenthal 1963,p. 29]); he drank heavily; completedonly 11 years of schooling; wasdomineering and jealous. Shefeared he would be "ugly" to herbecause she had so often rejectedhim, and she still carried a torch foran earlier love. Henry persisted,agreed to change to meet her objec-tions, and Gertrude began to lookfor his good qualities. Despite hercontinuing misgivings, she was per-suaded to marry him.

For a while, their marriage wasrelatively pleasant, but differencesin outlook and temperamentbecame troublesome. From thestart, there were sexual problems:Henry had "occasional seizures"during intercourse, and after awhile Gertrude put a pillow overher face to prevent his biting her.He was insensitive to her sexualneeds and "was either repelled orfrightened if she showed any sexualinterest." He knew Gertrudewanted children, but he did not."The least family that a person canhave, the better he's able to getalong," he had asserted before mar-riage; after marriage, "one of hiscontinuing concerns was thatGertrude would become pregnant"(Rosenthal 1963, p. 34).


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Birth and Early Life of the Quad-ruplets. In the third year ofmarriage, Henry's worst fears wererealized: Gertrude was pregnant.Hers was a difficult pregnancy,both physically and psychologically.Henry reported later that he dideverything he could to help her;she felt that he neglected her andwas deserting her. Her early preg-nancy was dominated by "nervouschills," backache, vomiting, loss ofappetite, weight loss, faintness, anddifficulty with urination. She beganto bleed lightly and stayed in bedfor 7 weeks. Her doctor told hershe was "too sympathetic with her-self," and her husband agreed.Gradually she began to feel better,to be able to eat more, and to gainweight. But her body became sounwieldy that she was virtuallyhelpless. Henry, fearful that shewould die, was kind to her andspent more time at home with her.Mrs. Genain was 31 years old; herhusband, 42.

The babies, born within a timespan of 17 minutes, presented facefirst; and each required internalpodalic version. Time, weight,length, and order of birth of thebabies are shown in table 1. Therewere feeding problems: Mrs. Gen-ain's milk, though plentiful, wasnot rich enough and had to be sup-plemented by gavage feeding.Hester could not suck and lostweight, and Iris, too, seemed not tosuck, though she worked hermouth and licked the breast. Bottlefeeding supplanted breast feedingfor Nora, Iris, and Myra on day 19;despite her difficulties with thebreast, Iris had no trouble with thebottle. Summarized in table 2 is thefeeding history for the quadrupletswhile hospitalized.

Nora and Myra were ready fordischarge on day 35, and, althoughthere was no such provision for

Table 1. Birth data

Time ofWeightLength

Table

birth

2. Feeding

Nora9:20

4 Ib., 8 oz.17"

history

Nora

Iris9:25

3 Ib., 5 oz.16"

Iris

Myra9:30

4 Ib., 4 oz.16'A"

Myra

Hester9:37

3 Ib., 0 oz.13V

HesterBreast feeding Day 1'Gavage only Day 1Gavage & breast Day 7 UnspecifiedBottle feeding Day 19 Day 19

Day 1Day 1

Day 7 UnspecifiedDay 19 Day 42

'Day on which a given feeding method was implemented.

Iris, she no longer had a feedingproblem and presumably mighthave gone home too. However, allfour were retained in the hospitaluntil Hester was put on bottlefeeding on day 42.

After 6 weeks, all were deemedto be in good condition and weredischarged. Weights at dischargeare given in table 3.

The parents' reaction to the birthsof their daughters were as disparateas had been their attitudes towardhaving children:

Mrs. Genain: What a wonderfulcreation ... I thought if the Lordwill only give me the strength toraise them, I have special work todo ... I hoped Henry would likehis own. [Rosenthal 1963, p. 42]

Mr. Genain: Of course I wasafraid. I didn't know how I was

Table 3. Weights at discharge

supposed to take care of four. ButI was worried about my wife,that she would die, and thenwhat would I do with four girlswithout a mother? [Rosenthal1963, p. 42]

Mr. Genain also worried aboutpublic reaction to multiple birth:"Oh, what will they think my wifeisa bitch dog?"

The minister of their churchreported that Mr. Genain "didn'thave much to say, but he gave asfine an exhibition of stammering asI've ever heard" (Rosenthal 1963,p. 43). Mr. Genain's brother alsosaid that Henry was greatly upset,saying, "What will people think Iam?" (Rosenthal 1963, p. 43) Butthe brother also felt that becausethere was such a fuss made overthe quadruplets, Henry got over hisfeelings of disgrace.

Weight Weight gainNoraIrisMyraHester

6 1b., 15 oz.5 Ib., 3oz.6lb., 4oz.4 Ib., Ooz.

2 Ib., 7oz.1 Ib., 11 oz.2 Ib., Ooz.1 Ib., 0 oz.


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The girls and their parents were"adopted" by their home town,Envira, which both flaunted andexploited them. The Envira Neil'sran a baby-naming contest. Com-peting companies offered freesupplies, and when one company'soffer was accepted, other com-panies were offended. But timeswere hard, and promised gifts wereoften not forthcoming. Mr. Genaingrew bitter at "the image of aneedy family [and] a bewilderedand economically inadequatefather" (Rosenthal 1963, p. 356).

In the home, Mrs. Genain quicklydeveloped a routine based on theprinciple that all of the quadrupletsshould be treated equally, and"equally" meant "identically." Herefforts to apply this principle, webelieve, often had the effect of pro-moting competition and jealousy.Hester (last born, weighing least atbirth, slowest to develop) sufferedmost, for there was the expectationthat all would be equal, physically,intellectually, and in personality.

Competition, jealousy, and envywere paramount in family relation-ships. The girls were constantlypushed toward one another forsocial interaction. Their father waselected constable "on the quadrup-lets ticket," and perceiving that hisclaim to fame and even to a job layin protecting the integrity of thegroup, he fenced the small yardand forbade his daughters to playelsewhere or to invite in otherchildren.

Within the group of four, therewas a hierarchy based initially onbirth order, but supplanted in timeby presumed or perceived abilities.

1. Norn: first born and first in allmeasurable physical attributes;designated leader andspokesperson for the group;highest in IQ; with best grade-

point profile; the first to get ajob. Retained Rank 1.

2. Iris: second born, but third inmost measurable physicalattributes; third in IQ; third bestgrade-point profile; third to get ajob. Fell to Rank 111.

3. Myra: third born, but second inmost measurable physicalattributes; second in IQ; secondbest grade-point profile; secondto get a job. Rose to Rank II.

4. Hester: last born and last in allmeasurable physical attributes;lowest IQ, poorest grade-pointprofile; was removed fromschool after 11th grade; neverhad a job outside the home.Finished where she started: RankIV.

It was primarily on the basis ofgreater physical similarity that Myrawas paired with Nora as the supe-rior set of twins; and although Iriswas, in fact, more like Nora orMyra, she and Hester constituted aresidual pair, the inferior set oftwins. Iris, in a sense, lost herbirthright to Myraa fact that hasnot ceased to rankle.

All four were overprotected andoverrestricted throughout their livesby their father and motherevenwhen three of them were workingand contributing to the family cof-fers. None of them ever reallydated, and they had no friends(only acquaintances). Though politeand agreeable, they had no socialskills. They were outsiders. Mr.Genain urged his daughters to staytogether while they could, for theywould be separated all too soon.Mrs. Genain, while professing towant more freedom for the girls,also felt the need to placate her dia-betic, irascible husband; shesuggested that they must mollifytheir father, that they were youngand "their time would come."

Initial Hospitallzations, NIMHYears, and Followup (1952-80)Nora. Nora became overtly psy-chotic in 1951 at age 21, resignedfrom a position she had held for 2years as a stenographic clerk, andwas hospitalized for psychiatric ill-ness 14 months later, at age 22.From 1952 until her admission toNIMH in early 1955, Nora was hos-pitalized four times for periods of24 months and received a total of19 electroshock treatments. Duringthe 3-year NIMH hospitalizarion,she was described as withdrawn,hallucinatory, delusional, and slowof speech, with a diagnosis of"schizophrenic reaction, catatonictype." After her discharge fromNIMH, she was transferred to aState hospital where she remainedfor 18 months. She then lived withher mother and held a series ofclerical jobs in each of which initialsuccess rapidly deteriorated. Sheremained out of the hospital until1967, at which time she spentanother year at NIMH. She hasbeen an outpatient in her homeState since 1967, except for 4months in 1979. She has been livingin a family care home and, mostrecently, in her mother's home.

Iris. Within 7 months of Nora'shospitalization, Iris, too, was firsthospitalized at the age of 22. Hersymptoms included numeroussomatic complaints, insomnia, thebelief that she was being watched,auditory hallucinations, and postur-ing. (Her resignation from her jobhad followed Nora's by 6 months.)Before her admission to NIMH, hertherapy had comprised a total of 67electroshock treatments. During the3-year NIMH admission, her diag-nosis was "schizophrenic reaction,catatonic type." After her stay atNIMH, she was transferred to a


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State hospital where she remainedfor more than 12 years. In her last 2years as an inpatient, an unsuccess-ful attempt was made to train heras a beautician; and she was placedin a halfway house in a city nearthe hospital. She required two sub-sequent, short-term hospitalizationsin 1977 and 1979 and, since then,has been living in a foster carehome and attending a day carecenter.

Myra. Myra was first diagnosed asschizophrenic (catatonic subtype) in1955 during the first NIMH evalua-tion of the quadruplets. Hersymptoms included marked psycho-motor retardation, hysteroidsymptomatology, multiple somaticcomplaints, and periods of depres-sion and anxiety. She held.a fewclerical jobs in the Washington, DC,area subsequent to the NIMH hos-pitalization while living in ahalfway house. She married in 1966and is the mother of two sons, ages16 and 23.

Myra received no medication andappeared to be functioning withoutpsychiatric problems until 1976,when she became paranoid anddelusional about her new employerand job. She was admitted to aState hospital for 2 months, wastreated with trifluoperazine, andreported that her symptoms lastedonly 4 months. She returned to sec-retarial work in 1978. In April 1979,she again developed an acute para-noid psychosis following familystress, attempted suicide by anoverdose of medication, and wasplaced under outpatient psychiatriccare. During this period, she wason a low dose of trifluoperazine.She had a brief 3-week hospitaliza-tion in April 1980 for difficultiesrelated to parkinsonian side effectsof the medication and, in October1980, reportedly again attempted

suicide by an overdose ofmedication.

Hester. Although the first NIMHhospitalization was her first hospi-talization, Hester apparently hademotional and functional problemsfor a number of years, resulting inher withdrawal from high school atthe end of 11th grade. She wasdescribed as "fearful, withdrawn,irritable, confused, and later halluci-natory" (Mirsky et al. 1987, p. 85).By the time she was 24, she wasclearly psychotic and was diag-nosed as having a "schizophrenicreaction, catatonic type" during her3 years at NIMH. She was trans-ferred in 1958 from NIMH to a Statehospital, where she remained untilOctober 1970. Although her coursehas remained chronic and unremit-ting, for the past 15 years she hasbeen maintained on medication asan outpatient.

In Rosenthal's summary of thelife history and test data obtainedon the Genains, he suggested thediathesis-stress theory as a reason-able way of accounting for thevariations in the severity of theirpsychiatric illnesses. Although theyshared an identical heredity(diathesis), differences in the waythey were treated by their parentsand significant others in theirenvironment led to different expec-tations and self-concepts and,consequently, to different phe-notypic expressions of theschizophrenic disorder.

Early physical and developmentaldifferences provided a rationale fordividing the set of four into twosets of identical twins. The morecompetent pair, Nora and Myra,were more favored and fussed over.Iris, second-born and physicallycloser to Nora and Myra, was mostoften bracketed with Hester, thesmallest and physically the least

prepossessing. Hester and Iris,treated as the less competent andcapable pair, more or less fulfilledthat expectation. This is a greatlysimplified and abbreviated but rea-sonably accurate summary of theearlier view of the Genains.

Family History Between 1963and 1981 (From Quinn,Unpublished Manuscript)During the 18 years following pub-lication of The Genain Quadruplets(Rosenthal 1963), Rosenthal andQuinn maintained contact with theGenains, following (with but fewexceptions) a schedule of springand autumn visits, which includeda 2-day stay in the hometown and avisit to the hospital or one of itssubsidiary facilities when one (ormore) of the quadruplets was insti-tutionalized. Data from these visitsderive primarily from observationsof and informal interviews with thesubjects and their mother, supple-mented by hospital notes andsummaries, interviews with psychi-atrists, social workers, and nurses,and occasional contacts with socialand business acquaintances of thefamily. Mrs. Genain sometimes doc-umented her accounts with lettersfrom one or another of her daugh-ters; between visits, letters from thequadruplets and telephone conver-sations with Mrs. Genain providedcontinuity. What follows is anattempt to abstract from these dataa brief account of the clinical courseof each of the subjects as revealedin their daily lives in interactionwith one another and others.

Particularly relevant to their prog-ress was Mrs. Genain's abidingconcern for the future of her daugh-ters. She was sensitive to that pointof view in psychiatric theory thatwould hold her responsible for their


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illness, but her defenses werestrong. She "knew in her heart"that she had done her best. Thatbest might have contributed to herdaughters' illness, but she couldnot countenance any suggestionthat she had favored one girl overanother. Her timetable for thefuture specified an order in whichshe would help her girls, one byone, to return to public life.

Mrs. Genain's program had Myra(now married) ensconced in herown home, while Nora (on con-valescent status) would for sometime live with her mother, workingand contributing to the mainte-nance of the home and herhospitalized sisters. With Nora liv-ing independently, or at least wellenough that the presence of a con-valescent sister would not bethreatening, Iris could have herchance and eventually Nora and Iriswould be able to attend to theneeds of their chronically hospi-talized sister, Hester.2

Mrs. Genain's program seemedhopeful and plausible, but factswere real and uncompromising.Before the end of the year, a photo-graph of Myra accompanying twoletters from her husband, John, toMrs. Genain was all too reminiscentof her posture and countenanceduring previous periods of extremepsychomotor retardation; and,when a few months later, Myrareturned to her mother's home withher husband and baby boy, she wasclearly incapable of caring for herchild. It appeared, too, that Irismight be able to leave the hospitalbefore Nora could either move onor tolerate the presence of hersicker sister. While Mrs. Genain felt

This scheme, while overly ambitiousand optimistic, was an accurate reflec-tion of the relative prognosis of herdaughters as diagnosed by clinicians.

it would be wrong to have Noraand Iris at home simultaneously,she could see no alternative. Myra'sarrival compounded the pressure,for with Iris pushing to come homeand Nora already there, Mrs. Gen-ain's carefully laid plans for thefuture were sharply threatened.

The present was difficult enough.Financial resources were dwindling,and only Nora was contributing tofamily funds; this was a modestcontribution to be sure, but withoutit, Mrs. Genain said, "I just don'tknow how we'd get along."

Nora's sisterseven Myrawerefinancial liabilities. Iris and Hestermade constant small demands onfamily resources, and, when deeplydisturbed, were destructive of theirclothing and other possessions. Fur-ther, if the past held an omen forthe future, Myra's visit was likely tobe costlyand so it was: Johnsquandered money on liquor, lostmoney when drunk, and Mrs. Gen-ain paid for many things for "BabyAndrew."

The competitive aspect of Nora'sillness, long recognized, butespecially virulent when she feltthreatened, became increasinglyevident.-1 Greatly disturbed at theprospect of Myra's visit, she com-plained that the house would benoisy and that Myra and the babywere coming home to drive her out.She had been upset by Myra's mar-riage and subsequent pregnancy:Myra was in the lead, and Noracould not catch up. Mrs. Genainfeared that if Iris came home, evenbriefly, Nora would feel that Iris,too, had outstripped her, for Norahad regressed enough that shecould not work and had taken sickleave from her job.

^t should not be assumed that Norawas alone in her competitiveness; allfour of the sisters exhibited this trait.

More trying and pervasive thanproblems of money and health werethose of behavior, most of whichreflected faulty, inadequate, or diffi-cult interpersonal interactions.Within the group of four, competi-tiveness, envy, and jealousythreatened every interpersonalinteraction. It might be easy to infersome sort of gain to the mother inher daughters' constant vying forher attention. Nevertheless,however rewarding to her their jeal-ousy and dependency might havebeen in the past, these traits hadbecome burdensome over the years,and Mrs. Genain often citedinstances of such behavior as obsta-cles to her efforts to help herdaughters. She understood thatsuch immature behavior was detri-mental to her daughters'relationships outside the family,and she deplored that fact; but shewas distraught when that samekind of behavior threatened inter-quadruplets relationships. When itappeared that Myra might bring herbaby home for an extended stay,she feared the consequences of hav-ing Nora and Myra at home at thesame time; but she knew that ifMyra should decide to come, "thereisn't but one thing 1 can do."

Particularly troublesome was thearea of sexual behavior. Hester,long perceived as "a sex maniac,"was no longer alone in alarmingsexual behavior. In Nora's casebookat a local State hospital were manysexual incident reports. Iris andHester constantly vied with oneanother for masculine attention,and Iris' intermittent plunges intodeep depression and psychoticbehavior were seen as stemmingdirectly from defeat in amorouscompetition with Hester. Hester,for her part, was neither unre-strained in triumphant joy, nor wasshe abashed when Iris explained


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that Hester had won "because shewill do things [with men] that Iwon't do."

Sexual acting out continued afterNora had returned to her mother'shome. The problem was in a sensecontained when she became emo-tionally and sexually involved with"Artie de Witt/' a long-time neigh-bor of the family whose childrenwere contemporaries of the quad-ruplets. At first, Mrs. Genaindisplayed a certain reticence inrevealing the nature of the relation-ship. She let us know that Norawas pursuing Art and that she dis-approved, but she asserted that Artalways behaved properly. Later sheindicated that Art's interest mightbe sexually tinged, and finally dis-closed that Nora was heavilyinvolved in a sexual affair with Art.

Nora demanded that Art be bothlover and father, and it is likely thatshe insisted that he, like her ownfather, should favor Nora over allothersincluding not only her sis-ters but his daughters as well.There may even have been somerivalry with "Mother"Art's wiferepresenting "Mother" in this case.And, as Mrs. Genain had toleratedand made excuses in her own fam-ily for Mr. Genain's fondling Nora,Mrs. de Witt was a "patient" and"understanding" person whoadvised Nora in many areas ofbehavior, yet condonedor at leasttoleratedMr. de Witt's liaisonwith Nora.

It is probable that financial con-cern led to Mrs. Genain's reluctantconsent to this liaison, but she citedother factors. Not sure that Noracould handle (or achieve?) dating atthis point, Mrs. Genain hoped that,in her association with Art, Norawas learning something about howto get along with men. Further, Artwas a safe date,"4 and the fringebenefits to the Genain family were

enormous: Mr. de Witt oftenbrought groceries to the family,provided transportation for Noraand her mother to visit Iris andHester when they were inpatients,and gave his time and energies tomaintenance of the house. Mrs. deWitt told Mrs. Genain that her hus-band "would always have someprotege" and might better bespending his time and money onthe Genains than on anyone else,for she felt this association was"helpful to him."

Their behavior with respect toArtie provides a striking example ofthe compulsion of the quadrupletsto behave like one another andtheir intense jealousy or siblingrivalry. Their mother has said theyhad thought that what one did, allmust do. Certainly Myra wasinvolved in this pattern, for whenshe married and thus had a man,her sisters' response was not one ofunalloyed )oy. Nora was outwardlyeffusive.5 Hester said ruefully that itwas "nice" for Myra; Iris, alwaysmore forthright, stated emphaticallythat Myra should have waited forher sisters: 'There should havebeen a quadruplet wedding."

Myra's marriage was too difficultan act for her sisters to follow, butNora set a pattern soon shared firstby Iris and then by Hester. Nora'sinfatuation with men had been asource of concern to hospital staffas well as to her mother but, as faras was known, sexual intercoursedid not occur until her affair withArthur de Witt. Nora, whatever herinitial craving, did not enjoy sex,harbored strong feelings of guilt,

4Mr. de Witt, at his wife's insistence,had undergone sterilization after thebirth of their fourth child.

^She was delighted to be Myra's maidof honor; neither Iris nor Hester wasable to attend the wedding.

and again became very sick. Shewas unable to work, and after anextended sick leave from her job,was again accepted at NIMH fortreatment. In her absence, Irisbecame Artie's sexual partner, asdid Hester. Mrs. Genain was a con-stant and pivotal figure in ahousehold which at any given timeconsisted of one to seven members:Mrs. Genain, one or more of herdaughters, and one or both of hergrandsons. (Myra's husband, JohnKimbark, sometimes visited for aslong as 2 weeks, but he neverresided there.) Mr. de Witt wasanother constant whose influencewaxed and waned over the years.

The explanation offered byRosenthal and his colleague,Quinn, thus stressed differential lifeexperiences as the major factor inthe differential severity of the disor-der among the Genains. While thecogency of that explanation remainsundiminished, it is neverthelessconceivable that biological factorscould also have contributed to thevariable outcome among the Gen-ains. New measures for assessingcerebral integrity, as well as a hostof other biochemical measures ofputative importance for normal anddisordered behavior, had beendeveloped since the late 1950's.Consequently, in the spring of1981, the Genains were invited toreturn to NIMH for additionalstudy. Rosenthal and Quinn hadmaintained close contact with thequadruplets over the years and hadurged that the Genains return forfurther studies employing newlydeveloped techniques. Theyreturned, accompanied by their 82-year-old mother (since deceased)and, for part of the stay, by Myra'shusband and two sons. The returnvisit lasted approximately 3'^months; during this time, the Gen-ains were tested with virtually the


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full battery of neurobiological testprocedures that have evolved overthe last 25 years.

Three independent diagnoseswere made on each patient, twousing Research Diagnostic Criteria(RDC) (Spitzer et al. 1977); and, inthe medication-free period, the psy-chiatrist responsible for the care ofeach patient made a DSM-III diag-nosis (American PsychiatricAssociation 1980). These diagnoses,together with the discharge diag-noses, appear in table 6. Withrespect to neuroleptic clinicalresponse, Nora, whose subtypediagnoses were consistently"chronic undifferentiated," showedthe greatest response. Iris, too, wasconsistently given the subtype diag-nosis "chronic undifferentiatedsubtype," but with the addition of"paranoid features" in one of theRDC diagnoses; her neurolepticclinical response showed "minimalchange in thought disturbance andwithdrawal." Myra was diagnosedonce as having a "schizoaffectivedisorder" (RDC), and was diag-nosed "schizophrenia, residualtype" on the other two independ-ent diagnoses (RDC and DSM-III);her neuroleptic clinical responsewas "worse on medication." Hes-ter's two RDC subtype diagnoseswere "chronic undifferentiated"and "residual," the latter designa-tion being supported by the DSM-III diagnosis of "residual type"; herneuroleptic clinical responseshowed a favorable "change indepression and thought disturb-ance" (DeLisi et al. 1984, table 4).

While inpatients, the quadrupletswere ranked on selected variablesfrom a Community Care Schedulewhich took into account reactions tosocial and community environmen-tal factors. Responses were scaled1 = adequate, 2 = fair, 3 = poor,and 4 = grossly inadequate. Result-

ant ranks showed Nora's responseto be the most nearly adequate andHester's response to be second inrank. Iris and Myra shared thirdplace. None had a global rankindicating a grossly inadequateresponse (DeLisi et al. 1984, table2).

The neurobiological proceduresincluded biochemical determina-tions from blood, urine, andcerebrospinal fluid of various cate-cholamine compounds withparticular emphasis on dopamineand norepinephrine; proceduresrelated to the identification of possi-ble preexisting viral infection of thecentral nervous system (these werenegative); neuroradiological andneurophysiological tests (computedtomography, positron emissiontomography, event-related potentialand electroencephalographic brainmaps, brainstem auditory evokedresponses (a measure of the integ-rity of the brainstem auditory relaynuclei); and an exhaustive batteryof psychological and psychometrictests, with a special focus on themeasurement of attention, arousal,and memory. Two of the tests wereessentially identical to measuresemployed in the late 1950'stheContinuous Performance Test ofsustained visual attention (Rosvoldet al. 1956) and the reaction timeparadigm (Zahn and Rosenthal1965). Further, for most of thebehavioral tasks, the Genains wereexamined both on and off medica-tionthe latter test occurring after aperiod of at least 2 weeks free fromthe phenothiazine drugs they weretaking on admission to NIMH. Thefull report of those tests appears ina series of detailed articles(Buchsbaum et al. 1984; DeLisi et al.1984; Mirsky et al. 1984). What fol-lows is a synopsis of the mostpertinent and salient of the fol-lowup data.

The 1981 Followup Study

Arrangements were made for othermembers of the Genain family aswell as Myra's husband to be evalu-ated as NIMH outpatients. Thesisters were then hospitalized on aresearch ward of the Adult Psychia-try Branch, NIMH, at SaintElizabeths Hospital, Washington,DC, for a medication-free evalua-tion. They were maintained free ofneuroleptic medication for a periodof 6 weeks.

Test Results.6 Three of the 1958psychological tests were repeated in1981: the Continuous PerformanceTest or CPT (a measure of sustainedvisual attention; Rosvold et al.1956), -a series of reaction time (RT)tasks as described by Zahn et al.(1981), and the Rorschach Test.Other attentional measures (RTcrossover and Stroop test) were alsoused in 1981. Results of the com-parisons between the 1958 and 1981tests are presented in table 4. The

'The following measures of attentionwere employed:

Reaction tune (RT) set index The subjecthad warning or preparatory intervals(Pis) of 2, 4, and 8 seconds before theimperative or "respond now" stimuluswas presented. The RT data were com-bined into a single weighted average or"set index" (Zahn and Rosenthal 1965)to consolidate the information. This test-ing procedure was virtually the same asthat used by Rosenthal (1963) during thefirst NIMH admission of the Genains.RT crossoivr. In this method, a series offour trials, all isotemporal (with thesame PI), was presented in the contextof a larger random series of tnals inwhich Pis varied from 0.5 to 11 secondsThe extent to which the subject can ben-efit from the regularity in this smallregular series and begin to respondmore rapidly is the operational measureof set (Steffy and Galbraith 1974). Three


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Table 4. Tests performed In 1958 and 1981 on the Genalnquadruplets

QuadrupletMyraNoraIrisHester

MyraNoraIrisHester

MyraNoraIrisHester = untestable; *reaction time

1958 examina-tion % correct

responses

CPTCPT AX

X task task89.4* 72.528.7 27.5

1.3 3.3

RTGlobal

assessment

NormalImpaired

1981 examination% correct responses

CPTXtask

On Offmeds meds82.0 78.798.7* 25.398.0* 64.780.7 27.3

SetOn meds

312*323*273*526

CPTAX task

On Offmeds meds30.8 35.880.8* 21.780.0* 56.742.0 13.3

RTindex

Off meds771

2113

Mean rank based on standard Rorschach determinants(see text)

Mean rank,1958

1342

Mean rank, 19811324

Rank change00

+ 2- 2

= scores within the normal range CPT Continuous Performance Test RT >

table and the description of thefindings are adapted from Mirsky etal. (1984). The CPT scores (percentcorrect responses) refer to the per-centage of critical stimuli respondedto correctly within the allowableresponse time of 0.7 seconds. Nor-mative data for this form of theCPT are provided in Rosvold et al.(1956), Mirsky (1960), and Mirskyand Orzack (1980).

On the first examination (1958),only Myra was capable of perform-ing the CPT (and within the "poorCPT" range), a finding similar tothose in previous reports of schizo-phrenic patients by Orzack andKornetsky (1966). Nora seemedbarely able to grasp the concept; Iriscould scarcely respond quicklyenough to make a few correctresponses, whereas Hester wasunwilling even to attempt to per-form. By contrast, in 1981, whentested on medication, all thewomen performed reasonably wellon the X task. Nora and Iris per-formed, in fact, within normallimits on both the X and AX tasks.Hester performed at an impairedlevel, but well enough to indicatethat both the concept and psycho-physical coordination were withinher gTasp. Myra's 1958 and 1981 Xtask scores were almost identical;her AX performance was markedlylower in 1981. She rarely performedwithin the normal range but was lit

isotemporal series with Pis of 3, 7, and11 seconds were used. All stimuli wereauditory. A so-called crossover measurewas calculated, defined as the differencebetween the first trial RT and those atthe three succeeding regular trials of thesame PI within the isotemporal four-trialseries.Continuous performance test (CPT). The Xand AX tasks of the CPT were admin-istered to all subjects. The X taskrequires the subject to press a responsekey whenever the letter X appears on a

video display but to withhold pressingfor other letters. In the AX task, the crit-ical stimulus is the letter X immediatelypreceded by the letter A The param-eters of the standard X and AX tasks

i are: stimulus duration = 0.2 seconds,interstimulus interval (1SI) = 1.0 sec-onds, allowable response time = 0.7seconds, total stimuli = approximately600, total critical stimuli = 150 (X task)and 120 (AX task).The Stroop test (Stroop 1935; Jensen1965). This procedure involves the pres-

entation of three stimulus displays via aslide projector. In the first slide, colorpatches are the stimulus material, andthe subject is required to name the col-ors. The second slide presents colornames printed in inks that match thelexical content, whereas in the thirdslide, the color names and the inks donot match. The difference in timerequired to read the color names onslides 2 and 3 is thought to reflect sus-ceptibility to interference anddistraction.


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tie affected by withdrawal ofmedication. When tested off medi-cation, Nora and Hester showedvery large decrements in perform-ance on the CPT. Iris showed amore modest deficit.

Much the same effects were seenin the RT task. In the global assess-ment of the Genains' RTperformance, their ranking wasidentical to that which theyachieved on the CPT in 1958: nor-mal performance only in Myra;attempted performance, albeitimpaired, in Nora; and essentiallyno scorable effort in Iris and Hester.As with the CPT, the RT in 1981(on medication) was substantiallyimproved. RT was essentially nor-mal by the set index metric inMyra, Nora, and Iris. AlthoughHester's performance was slow, itwas nevertheless a reasonableeffort. When the quadruplets weretested off medications, major deteri-oration in RT occurred in all fourwomen. Neither Nora nor Hestercould sustain RT values below oreven close to 2,000 milliseconds.

The results on the attentionaltests suggest strongly that the psy-chological impairments in memoryand learning (e.g., figure 1) that fol-lowed the withdrawal of medicationfrom the Genains could be attribut-able to the secondary effects ofimpaired information processing.This result is consistent with theview that impaired attention is acore symptom in the syndrome ofschizophrenia. This theme has beendeveloped by one of us in anothercontext (i.e., Mirsky and Duncan1986). It was suggested there thatpoor attention could be at the basisof poor coping skills, intrafamilialconflicts and communicationdeviance (Singer and Wynne 1966),difficulties in communicating withthose outside the family, andincreased isolation.

The question arises as to whetherthe suggestion concerning thepathogenic effects of poor attentioncould be applied to the discordantlife outcomes of the Genains. If wehad used the 1958 CPT scores (table4) as a measure of basic attentivecapacity, we would have predictedthat only Myra would have had achance to develop a normal life.Although Iris and Hester were notin the running at all, the borderlineCPT scores of Nora could have sug-gested the possibility of a lifeoutcome other than intermittentinstitutionalization. In general, the

life histories of the Genains supportthis simplistic formulation, sinceonly Myra has had a near-normalexistence; and Nora has had peri-ods of modest occupational andinterpersonal success. However, thedata of figure 1 weaken somewhatthe case about the central role ofattention. Considering both on-drugand off-drug scores, one would behard put to predict a better out-come for Myra than for Iris.Possibly, the pronounced improve-ment in Iris' attention produced bymedication (even in the off-drugstate) came too late in her life to be

Figure 1. Representative tests of attention and memory in theGenain quadruplets, on and off medication

oUJ

100

o 8M

100< cci- 5=Q. Oo o

.0040

^ .0024K

.0008\M

n l ! iLjl IlkN H M N H M

0.oocto

.020 r

.040 -,

10

M

a ON OFF

DRUG DRUGThe score used in the Stroop test is the reciprocal of the time required to read the names with con-trasting lexical and color content The reciprocals (of the set index) are also plotted In the case of thereaction time (RT) scores Memory 1 consists of free recall of related series of word Ksts, Memory 2is prompted recall of these fists. CPT = Continuous Performance Test.


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VOL. 14, NO. 4, 1988 605

useful; she could not escape thecrushing effect of the diathesis andof the negative familial expecta-tions. We are making the inference,based on the improved level of per-formance Iris showed in theunmedicated state in 1981; that 25years of phenothiazine treatmenthas produced a relatively perma-nent enhancement in herfunctioning, an enhancement that isevident even after she is withdrawnfrom medication. It is not possible,however, to exclude the effects oftime itself on the disorder.

The complexity of the previousRorschach information is difficult tosummarize here (Rosenthal 1963).What Rosenthal pointed out in 1963is still true: the Rorschach Test is acontroversial diagnostic instrumentthat nevertheless can provide tan-talizing views into the perceptualworld of persons with psychiatricdisorders. Although the validity ofthe Rorschach as a diagnosticdevice is still questioned by many,it was remarkably accurate in thehands of a clinician like MargaretThaler Singer, whose descriptionsof the Genain family members(Singer 1963) were startlingly accu-rate. The test was included in the1981 battery for the sake of com-pleteness and was used in thepresent instance primarily to com-pare rankings of the quadrupletsbetween 1958 and 1981. None ofthe records of the quadrupletsobtained in 1950 and 1960 wereseen as normal; all had varyingdegrees of what was referred to aspsychotic or organic psychopathol-ogy. The same is true of the presentRorschachs, obtained during themedication period. In 1981, theyappeared to be more cautious, con-stricted, and withdrawn than intheir earlier testing. Based on thestandard Rorschach determinants,the global impression created by the

1958 examination was that thehealthiest sister was Myra, followedby Hester and Nora, with Irisappearing the least intact. The 1981examination yields a somewhat dif-ferent global ranking: Myra is stillseen as the most intact, followednow by Iris and Nora. Hester nowappears as the least intact sister.These global evaluations are sup-ported by rankings based on meansobtained by summing and averag-ing the ranks from individualdeterminants (e.g., number ofresponses, percent of responseswith good form [F+%], and num-ber of human or movementresponses). Perhaps the most strik-ing changes are that Iris has movedfrom lowest average rank in 1958 tosecond highest in 1981, and thatHester's rank (which fell to lowestin 1981) mirrors her overall clinicalstate. Nora still stands third amongthe quadruplets.

Behavioral Tests, Medication, andthe Passage of Time. On all tests ofattention (CPT, RT, RT crossover,Stroop), the quadruplets functionedbetter on medication. When takenoff medication, Nora and Hestershowed greatly impaired perform-ance; for Myra and Iris, decrementsin performance were considerablyless pronounced. Figure 1 showsthe dramatic differences in responseto medication between Nora and

Hester, on the one hand, and Myraand Iris, on the other. It is impor-tant to note that even withoutmedication, the quadruplets as agroup performed better in 1981than in 1958.

Other Tests. The Luria-Nebraskaprovides a basis for comparison ofintellectual functioning in the twoperiods. This test, administered in1981, yields an estimate of full-scale(Wechsler Adult Intelligence Scale-Revised) IQ. The estimates are pre-sented in table 5, where they arecompared with scores on the Hen-mon-Nelson administered in 1947,when the quadruplets were 16years old, years before any of themhad received a psychiatric diag-nosis. It will be observed that the1981 estimates were markedly simi-lar to those obtained 35 yearsearlier. Only Iris' score differed bymore than 3 points from the 1947values.

Brainstem Auditory EvokedResponses (BAERs). As a group,the Genains showed significantslowing of conduction time, com-pared with age-matched controls(Buchsbaum et al. 1984). This find-ing of abnormality is furtherevidence for brainstem dysfunctionin schizophrenia, although as in thecase of the computed tomography(below), this measure does not dis-tinguish among the quadruplets.

Table 5. IQ scores, Genain quadruplets, ages 16 and 51

QuadrupletMyraNoraIrisHester

Henmon-NelsonIQ, age 16,

194687998977

Lurla-Nebraska(WAIS estimate), age 51,

198189978280

WAIS = Wechsler Adult Intelligence Scale.


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Computed Tomography (CT). AllCT scans were normal; there wasno evidence of ventricular enlarge-ment and little atrophy (Buchsbaumet al. 1984).

Smooth Pursuit Eye Movements.Subsequent to their discharge fromNIMH in 1981, measurements ofsmooth pursuit eye movementswere made at their home in Enviraby Dr. Deborah L. Levy. Samples ofthe tracings, presented in figure 2.,support the interpretation that thereis more organic "disturbance" inNora (top tracing) and Hester (bot-tom tracing) than in Iris and Myra.Since it has been established byHolzman, Levy, and colleagues(Holzman 1987) that neurolepticmedications do not alter this func-tion in schizophrenic patients, weare justified in ignoring medicationeffects.

Biochemical Measures. What fol-lows is a summary of the salientfindings of the extensive biochemi-cal measures reported by DeLisi etal. (1984). In general, the biochemi-cal results did not appear to berelated to diagnosis or severity ofillness in the Genains. Direct testsof the "dopamine hypothesis" (i.e.,that excess amounts of this trans-mitter characterize patients withschizophrenia) were negative. Noneof the dopamine metabolites exam-ined were found to be significantlydifferent from normal in any of thequadruplets. The same was true fortests of the level of the enzymemonoamine oxidase. Levels of thiscompound, which is important forthe metabolism of dopamine andnorepinephrine, did not differenti-ate the Genains from age-matchedcontrols. On the other hand, con-sistently lower levels of dopa-mine-p-hydroxylase (DBH), theenzyme that converts dopamine to

norepinephrine, as well as phenyl-ethylamine (PEA) to phenyl-ethanolamine, were found in the

quadruplets. Not surprisingly, per-haps, significantly higher titers ofPEA were found in all the Genains,

Figure 2. Smooth pursuit eye movement recordings obtained onthe Genains In their home in Envira

GENAIN QUADRUPLETS

NORA

STELAZINE, 20 mg

IRIS

CPZ, 100 mg.; Prolixin Decanoate, 1 cc.

MYRA

HESTER

MELLARIL, 200 mg.Note trie greater irregularities fn pursuit observed in Nora (top tracing) and Hester (bottom tracing)than in Iris and Myra. CPZ - chlorpromazine. Tracings courtesy of Dr. Deborah L. Levy.


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as well as in their mother. Whilenorepinephrine concentrations didnot distinguish the Genains fromcontrols, there were alterations intwo related functional measureshigher numbers of plateleta-adrenergic receptors than in con-trols, and reductions in a measureof cyclic adenosine monophosphate(cAMP) production, as comparedwith normative values.

According to DeLisi et al. (1984),these changes could all be linked toa related, but poorly defined, defectin aspects of the metabolism ofdopamine in the Genains.

Effects of Medication. Effects ofmedication, both positive and nega-tive, have been shown to differwithin the group: Myra and Insshowed less deterioration whenremoved from medication than didNora and Hester. Moreover, theyrecovered more quickly than Noraand Hester when the medicationwas changed. Nora and Hester, onthe other hand, show dramaticimprovement in functioning whenon neuroleptics, and the effects ofdeprivation of such help are notonly devastating but long-lasting.So it was that Myra and Iris werethe first to be able to return to theirhome town, with Nora and Hesterbeing retained several weekslonger. Thus, a new kind of pairingemerged: one determined by on/off-medication performance, which hasnot completely supplanted theearlier designated twinships anddoes not carry the same superior/inferior attached evaluations. ForMyra, clearly the most nearly ableto function "on her own," stillthinks of herself as more like Nora,the "twin" she nudged from leader-ship, while Iris and Hester remainlinked in their minds. It was notuntil the quadruplets returned toEnvira that the new pairing (i.e., of

Nora and Hester) began to exert aninfluence on practical livingarrangements which were solidifiedafter the death of Mrs. Genain.

The Genains Since 1981

At the end of the summer of 1981,Myra was happy and animated. Shenow had a new area of superiority:she did not need medication. Shehoped that with family therapy, sheand John would be able to providea home for their boys.7 John wasnot at all keen on participating intherapy, and that plan was aban-doned. Nora and Iris were planningto return to day care at a State-runfacility while living at home, andHester, though having some diffi-culty with stomach problems(thought to be related to medica-tion), was happy to be "helpingMama," whose health was steadilydeteriorating.

As long as she was physicallyable, Mrs. Genain maintained herhome for her girls. The story of thehousehold was one of continualtroubles: problems with the aginghouse; two burglaries; Iris's "com-plexes," which returned andworsened when she forgot to takeher medicine; Hester's recurringphysical problems; Myra's brokenleg; and Mrs. Genain's increasingillness (three hospitalizations in 1year).

Hn 1979 a series of difficulties dis-rupted Myra and John's alreadyprecarious marriage and family, andtheir boys were taken from them by thecourts. The younger boy is still in a fos-ter home and seems to be thriving; in1987 he graduated from high school.The older boy has finished a course indiesel truck maintenance and is seekinga job.

In March of 1983, Mrs. Genainwas hospitalized for the last timeand died of cancer a few weekslater. She was 84; her daughters,not quite 53. Myra, who spent mostof her life trying to escape beingone of the Genain quadruplets,now sought to be the head of thefamilythe bossbut Nora, Iris,and Hester all asserted that it wasNora who "kept things going."Nora, however, said that she wasnot equal to the task: "I'm checkingout apartments 'cause I can't takecare of this whole house bymyself."

Eventually Iris returned to a half-way house; Myra moved to hermother's house with her elder son(she and her husband separatedand each sued the other fordivorce, but their marriage remainslegally intact). Nora and Hesternow share an apartment under theauspices and supervision of Statemental health social services.

Summary and Discussion

The Genain quadruplets at age 57are functioning about as well asthey ever have in their adult lives.Their identical genetic endowmentis reflected in identical CT scansand similar biological and biochemi-cal abnormalities: delayedcomponents in the BAER, lowDBH, and high PEA (Buchsbaum etal. 1984; DeLisi et al. 1984).

For most of their lives they havebeen viewed as two pairs: Nora andMyra, and Iris and Hester. The dataobtained in their maturity and themarked effects seen when theywere taken off medication suggestthat there may be more similaritybetween Myra and Iris, on the onehand, and between Nora and Hes-ter on the other; the latter pairappear to show greater evidence of


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functional brain disturbance. In thisconnection, it may be significantthat Nora was the first born andHester the last. From an obstetricalpoint of view, a case could be madefor the first and last born to havesustained more brain injury thanthe other two.8 These observations,however, did not become salientuntil the Genains were studied atmaturity. In the neurological exam-ination, Nora and Hester had moresoft neurological signs (6 and 5.5,respectively) than Iris and Myra (2.5and 2.0, respectively).

For heuristic purposes, we canattempt to conceptualize the inter-active role of neurobiological andenvironmental factors in the out-come of the Genains. Figure 3,which is adapted from a recentreview of schizophrenia by Mirskyand Duncan (1986), shows thetheoretical relation betweenenvironmental stress and schizo-phrenogenic brain abnormality inthe development of schizophrenia.The quadruplets with putativelygreater brain abnormalities (pre-sumably aggravated during birth)are Hester and Nora; they appear tothe right of the figure. The womenwith less brain abnormality, Iris andMyra, are shown to the left. Thevertical position of the quadrupletswithin the diagram reflects the dif-ferences in life stress they haveexperienced. This impressionisticview of where the Genains wouldbe placed on a nature-nurture con-

"The facts pertaining to Hester's birthare in dispute (Rosenthal 1963, pp. 39-40), but her birth weight (1,361 g) isclearly indicative of greater prematuritythan her sisters' (Nora, 2,041 g, Myra,1,928 g, Ins, 1,503 g) Rosenthal specu-lated that "Hester may have sufferedhandicaps from which she was never torecover" (Rosenthal 1963, p. 544).

Figure 3. Schematic-impressionistic placement of the four Genainquadruplets on a joint stress x brain abnormality continuum

MORE

GCW>zLU

LESS

U NoSpectrum

~ Disorder

i l l i l l j LLESS MORE

SCHIZOPHRENOGENICBRAIN ABNORMALITIES (SBA)

tinuum summarizes much of theinformation contained within thepresent review.

In assessing the possible effectsof aging upon the expression ofschizophrenic illness in thesewomen, a number of other factorsmust be considered Medication hasreduced the severity of symptomsin Nora, Hester, and, to a lesserdegree, Iris. Myra's marriage hastaken her out of the Genain homefor varying periods of time, and atthose times there has been less tur-moil in interquadruplet interactions.Nora has finally abandoned allthought of becoming fullyemployed and self-sustaining, andwhile she may feel a sense of

failure in this respect, the concomi-tant reduction in pressure probablyrelieves some stress. Hester, thoughstill at the bottom in status withinthe group, has gained some impor-tance from a recent serious physicalillness and faces fewer demands forservice to other family members.

In her later years, Mrs. Genainappeared to grow more tolerant ofher daughters' disabilities. Whetherthrough a diminution of energy,sheer discouragement, or anincrease in wisdom, she no longerbelieved she could change herdaughters or make things right forthem. (In a poignant reminiscence,she recalled that she had refused todiscuss a motion picture contract


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for her girlswho were quite cele-brated in their childhoodbecauseshe wanted them to have a normallife.) These are but a few examplesof the kinds of changes which haveoccurred with the passage of time,but not necessarily as a result of theaging process.

It is by no means clear in the caseof the quadruplets that their schizo-phrenic illness has "burned out"with age. Without doubt, they haveimproved greatly since they werefirst admitted to NIMH in 1955, andat age 57, there is still time for fur-ther improvement.

A group of only four cases willnot allow us to confirm or contra-dict any hypothesis; however, thespecial nature of these four women(odds of occurrence of about one ina billion) gives us the right to spec-ulate that the schizophrenicphenotype and the course of itsexpression will ultimately be under-stood as a combination ofbiochemical abnormality, braindamage (both of which may begenetically determined), and lifestress (figure 3). The specific com-binations of factors leading to thevaried expressions of the illness isunknown, but may be revealedwith further study.

PostscriptAs we look back over 33 years of anunusually intimate professionalassociation with a family dominatedby schizophrenia, there are ques-tions and speculations that hauntour thinking, but for which ourvoluminous data provide no defini-tive answers.

1. Why, for example, was Myrafirst admitted to NIMH with a diag-nosis of schizophrenia (catatonictype)? Diagnosis of schizophrenia is

difficult, and specification of sub-type is slippery: behavioralsymptoms lose clarity as theychange with clinical state. Rosenthalnoted (1963, p. 518), that "the pat-tern of [subtype] diagnoses overtime with respect to each Quad isremarkably consistent," and his dis-cussion of schizophrenia and itssubtypes is sharply focused onimplications for heredity of schizo-phrenia. But it is also interesting toponder interquad similarities anddifferences in initial diagnoses.

2. The earliest diagnosis ofschizophrenia in the quadrupletswas that of Nora, then 22 years old:"acute schizophrenia." Iris' firstdiagnosis, nearly 7 months later,was "schizophrenia, acuteundifferentiated type." Nora'sfourth diagnosis, at 24 years of age,was "schizophrenic reaction,chronic undifferentiated"; Iris, atthat same time, was diagnosed"schizophrenic reaction, acuteundifferentiated." About 3'^months later, Iris had a fifth admis-sion to Alta Vista Hospitalwith a diagnosis of "catatonicschizophrenia."

3. Four months later, all four sis-ters, now only a few months awayfrom their 25th birthday, enteredNIMH Clinical Center with identicaladmitting diagnoses: "schizophrenicreaction, catatonic subtype." Nei-ther Hester nor Myra had hadprevious hospitalizations, and whileboth were clearly disturbed, andHester was by all accounts psy-chotic, Myra had been seen by thesame psychiatrist who had hospi-talized Nora and Iris and had beenassessed by him as having had an"acute period of depersonaliza-tion," but as not being psychotic. InRosenthal's judgment, Myra "maywell have successfully maintainedherself outside the hospital." Many

of the scientists associated with theNIMH study were puzzled by thediagnosis and felt, instead, that shewas experiencing a hysterical reac-tion to the illness of her sisters.Was this but another example ofthe compulsion to perceive thequadruplets as identical in allrespects? In any event, this addsemphasis to the discordant severityof the illness in these women ofidentical genetic endowment.

4. Is schizophrenia a single dis-ease entity with different subtypesrepresenting different clinically dis-cernible manifestations which arestages in the development of thedisease: catatonicundifferentiatedhebephrenic?g Table 6 lends generalsupport to this formulation, despitesome minor departures from it.

5. Is the illness course patternheritable? If we look only at man-ifest content of behavior of each ofthe quadruplets when diagnosedcatatonic, hebephrenic, etc.,heritability, not only of course pat-tern but also of manifestation ofsubtype, is strongly suggested. If,however, we take into account alifelong pattern of imitation amongthese women, together with a com-pulsion (at first imposed and laterinternalized) toward unity and uni-formity, to be alike, the evidence isclouded. Psychopathological charac-teristics were present in all:extremes of |ealousy and envy,ideas of reference bordering on par-anoia, social ineptness, immaturitynot far from infantilism, and more.But how are we to separateheritability from social learning in agroup of patients who were sociallyisolated, forced to depend upon

vFor a discussion of schizophrenia andits subtypes with reference to implica-tions for heredity, see Rosenthal (1963,pp 517-529).


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Table 6. Subtype

DateAugust 1952October 1952March 1953

June 1953October 1953January 1954

May 1954

September 1954

Admission2nd Admission

Discharge

Admission1

2

3

45

6

78, 9, 1011, 12

diagnoses of the

NoraAcuteAcute

Acute

quadruplets (arranged chronologically)Alta Vista diagnoses

Iris Myra

Acute undifferenti-ated

Catatonic?

Chronic undifferenti-ated

Chronic undifferenti- Acute undifferenti-ated ated

Catatonic

Catatonic

Catatonic

Chronicundifferentiated

Hebephrenicfeatures

Hebephrenicfeatures

Hebephrenicfeatures

UndifferentiatedUndifferentiated

Undifferentiated

NIMH diagnoses 1955Catatonic Catatonic


Catatonic CatatonicKenwood State Hospital diagnoses

Hebephrenic

Catatonic +hebephrenicfeatures

Catatonic +paranoid features

HebephrenicHebephrenic or

undifferentiatedHebephrenic or

undifferentiated

Hester

Catatonic

Catatonic

Hebephrenic

Undifferentiated

Undifferentiated

UndifferentiatedParanoid features

Hebephrenic

UndifferentiatedHebephrenicHebephrenic

features

(Continued on next page)


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VOL. 14, NO. 4, 1988 611

NIMH diagnoses 19811. Research Diag- Chronic undifferenti- Chronic

nostic Criteria(RDC)

2. RDC

3. DSM-III

DischargedDSM-III

ated




Affective component

undifferentiatedParanoid featuresChronic undifferenti-

atedChronic undifferenti-

atedUndifferentiated

(Paranoid)+ Affective features

Schizoaffective dis-order

Residual type

Residual type

Schizoaffective(Schizophrenia

residual)


Residual type

Residual type


Note.Table includes data from table 3 in Rosenthal (1963).

parents and one another for allaspects of social behavior? An oldfamily friend who visited theGenains just before their firstadmission to NIMH felt that thequadruplets had no experience indifferentiating the real from theunreal: "They were not brought upon realityall pretensePretendthey are rich, pretend they areinvited to high-class parties, and soon and so forth, and [the parents]got the girls pretending."

6. How reliable are the data fromour primary source, Mrs. Genain?We sometimes learned at a laterdate that her earlier reporting of anevent had been incomplete. Whenthere were occasional discrepancies,had she sought to deceive, or washer memory of events colored bythe context in which she relatedthem? We know that her assess-ments of the relative mental healthof her daughters were influencedby her attitude toward each at thetime she made her judgment. Shewas sometimes stung by what sheperceived to be ingratitude,defianceeven hatred; but we feltthat it was clear when such inter-personal difficulties or animositiescolored her judgments.

7. What long-term effects on thedevelopment of schizophrenia and

its course stem from what might betermed contingency decisions?These are "what if" questions.

What if Mrs. Genain had hada different physician during herpregnancy and delivery ... onewho was both more compassion-ate and professional in hisbehavior toward his patients.Rosenthal (1963, p. 557) reportsthat "Dr. Booth was a medicalmaverick who was forced out oftown by his own colleagues."Mrs. Genain felt that she wasneglected during her pregnancy,an opinion shared by Dr. Booth'scolleague and assistant, as well asby Mr. Genain. When she was inlabor and in great pain, he toldher she was "too sympatheticwith herself" and that she should"keep her thoughts to herself."He was clearly antagonistictoward Hester, and when sheand Iris were brought to himbecause the parents worriedabout their masturbation, Dr.Booth advised and performed cir-cumcision as a cure. A colleaguedescribed Dr. Booth as "quite aguy, but a ruthless surgeon" and"a most unstable individual." Formore on Dr. Booth, see Rosenthal1963.)

What if the little girls had

had other playmates and a nor-mal school experience?10

What if they had beenallowed to have dates?

What if Hester had been seenby the parents as troubled ratherthan as "bad," "the moron type,""a sex maniac"?

What if Myra had managed(as she wanted to) to move to theYWCA when her seriously ill sis-ters were at home?

These are but a few of theunanswerable questions that arisein contemplating the life circum-stances of the Genain quadruplets.Perhaps none of these things madeany difference, but if the diathesis-stress model has any validity, thesequestions and others like themmust, as far as is possible, be takeninto accountfor example, whatstressors, and in what degree, dideach of the sisters experience sim-ply as a result of having been amember of a set of identicalquadruplets?

One important "what if" remains:what if we had not maintained fre-

10When Iris was held back as a resultof having rheumatic fever, all wererequired to repeat the grade.


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quent close contact with thisfamily? We think we know theanswer to this one: there wouldhave been no followup study in1981.

References

American Psychiatric Association.DSM-111: Diagnostic and StatisticalManual of Mental Disorders. 3rd ed.Washington, DC: The Association,1980.Buchsbaum, M.S.; Mirsky, A.F.;DeLisi, L.E.; Morihisa, J.; Karson,C.N.; Mendelson, W.B.; King,A.C.; Johnson, J.; and Kessler, R.The Genain Quadruplets:Electrophysiological, positron emis-sion, and X-ray tomographicstudies. Psychiatry Research, 13:95-108, 1984.DeLisi, L.E.; Mirsky, A.F.;Buchsbaum, M.S.; van Kammen,D.P.; Berman, K.F.; Caton, C ;Kafka, M.S.; Ninan, P.T.; Phelps,B.H.; Karoum, F.; Ko, G.N.; Korpi,E.R.; Linnoila, M.; Scheinin, M.;and Wyatt, R.J. The Genain Quad-ruplets 25 years later: A diagnosticand biochemical followup. Psychia-try Research, 13:59-76, 1984.Holzman, P.S. Recent studies ofpsychophysiology in schizophrenia.Schizophrenia Bulletin, 13:49-75,1987.Jensen, A.R. Scoring the Strooptest. Ada Psychologica, 24:398-408,1965.Mirsky, A.F. Studies of the effectsof brain lesions on social behaviorin Macaca mulatto: Methodologicaland theoretical considerations.Annals of the Neio York Academy ofSciences, 85:785-794, 1960.

Mirsky, A.F.; DeLisi, L.E.;Buchsbaum, M.S.; Quinn, O.W.;Schwerdt, P., Siever, L.J.; Mann,L.; Weingartner, H.; Zee, R.;Sostek, A.; Alterman, I.; Revere, V.;Dawson, S.D.; and Zahn, T.P. TheGenain Quadruplets: Psychologicalstudies. Psychiatry Research, 13:77-93, 1984.Mirsky, A.F., and Duncan, C.C.Etiology and expression of schizo-phrenia: Neurobiological andpsychosocial factors. Annual Revieivof Psychology, 37:291-319, 1986.Mirsky, A.F., and Orzack, M.H.Two retrospective studies of psy-chosurgery. In: Valenstein, E.S., ed.The Psychosurgery Debate: Scientific,Legal, and Ethical Perspectives. SanFrancisco: Freeman, 1980.Mirsky, A.F.; Quinn, O.W., DeLisi,L.E.; Buchsbaum, M.S.; andSchwerdt, P. The Genain Quadrup-lets: A 25-year follow-up of fourmonozygous women discordant forthe severity of schizophrenic illness.In: Miller, N.E., and Cohen, G.D.,eds. Schizophrenia and Aging. NewYork: Guilford Publications, 1987.Orzack, M., and Kornetsky, C.Attention dysfunction in chronicschizophrenics. Archives of GeneralPsychiatry, 14:323-326, 1966.Quinn, O.W. "Observations on theFamily History of the Genain Quad-ruplets, 1963-1981." Unpublishedmanuscript, 1988.Rosenthal D. The Genain Quadrup-lets. New York: Basic Books, Inc.,1963.Rosvold, H.D.; Mirsky, A.F.;Sarason, I.; Bransome, E.D., Jr.;and Beck, L.H. A continuous per-formance test of brain damage.journal of Consulting Psychology,

20:343-350, 1956.Singer, M.T. A Rorschach view ofthe family. In. Rosenthal, D., ed.The Genain Quadruplets. New York:Basic Books, 1963. pp. 315-325.Singer, M.T., and Wynne, L.C.Principles for scoring communica-tion defects and deviances inparents of schizophrenics:Rorschach and TAT scoring man-uals. Psychiatry, 29:260-288, 1966.Spitzer, R.L.; Endicott, J.; andRobins, E. Research Diagnostic Crite-ria. New York: New York StatePsychiatric Institute, 1977.Steffy, R.A., and Galbraith, K.A. Acomparison of segmental set andexplanations of crossover pattern inprocess schizophrenic reaction. Jour-nal of Abnormal Psychology, 83:227-233, 1974.Stroop, J.R. Studies of interferencein serial verbal reactions, journal ofExperimental Psychology, 18:643-662,1935.Zahn, T.P.; Carpenter, W.T., Jr.;and McGlashan, T.H. Autonomicactivity in acute schizophrenia: I.Method and comparison with nor-mal controls. Archives of GeneralPsychiatry, 38:251-258, 1981.Zahn, T.P., and Rosenthal, D. Pre-paratory set in acute schizophrenia.journal of Nervous and Mental Disease,141:352-358, 1965.

The Authors

Allan F. Mirsky, Ph.D., is ResearchPsychologist and Chief, and OliveW. Quinn, Ph.D., is GuestResearcher, Laboratory of Psychol-ogy and Psychopathology, NationalInstitute of Mental Health, Beth-esda, MD.


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