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http://cpj.sagepub.com/content/13/7/581The online version of this article can be found at:

 DOI: 10.1177/000992287401300705

1974 13: 581CLIN PEDIATRJerome S. Harris and Richard H. Heller

The Detection of Klinefelter's Syndrome at Birth  

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581

ANOMALIES

The Detection

of Klinefelter’s

Syndrome at Birth

Jerome S. Harris, M.D.,*

Richard H. Heller, M.D.

From the Departments of Obstetrics and Gynecologyand Pediatrics, Sinai Hospital of Baltimore, Baltimore,Md.

* Valley Medical Center of Fresno, Fresno, Calif.93702.

This investigation was aided by Public Health ServiceGeneral Research Support Grant 5-S01-RR05478, andMaryland State Department of Health and MentalHygiene Grant 03-H-000,140-3.

A total of 2,176 newborn boy babies werescreened for the prospect of having Klinefelter’ssyndrome by comparing phenotypic sex andnuclear sex. A discrepancy between the

phenotypic sex and the nuclear sex, suggestive ofthe presence of the aneuploid karyotype as-

sociated with Klinefelter’s syndrome, was foundin seven babies, and confirmed by chromosomeanalysis. Despite the essentially normal physicalexamination typically reported at birth in babieswith Klinefelter’s syndrome, phenotypic hints ofthe presence of the disease in the form ofundescended or unusually hard or soft testes werenoted in three of the seven infants. Genetic

counseling of both the families and the pediatri-cians was only moderately well received, becauseof the seeming normality of the babies. Pediatri-cians should be aware that Klinefelter’s syndromecan be recognized at birth, and that geneticcounseling and long-term follow up are advisable.

KLINEFELTER’S SYNDROME, a dis-order of phenotypic males with concomitanthypogonadism and sterility, is diagnosableusually by physical examination from pu-berty on because of its associated endocrine,intellectual, and behavioral difficulties.

Cytogenetically, it is characterized by the

presence of at least one Y chromosome andone or more extra X chromosomes. Themost frequent karyotype is 47, XXY. Sexchromatin bodies (Barr bodies), representingthe extra X chromosome (s), can be demon-strated in cell nuclei of buccal mucosa smearsand preparations from other somatic tissues.Excellent detailed studies describing the na-ture and course of the illness, once it hasbecome clinically apparent, are available.’-&dquo;Its incidence is reported as about one in

every 700 newborn phenotypic males.9With the exception of some instances of

mosiacism, the aneuploid chromosome com-

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582

plement which is associated with Klinefelter’ssyndrome is readily demonstrable by full

chromosome analysis throughout life. Thisalso applies to the Barr bodies in somatic cellnuclei, which are not present in normal

males.

Through the striking phenotypic charac-teristics of the syndrome are not usuallyapparent until puberty, an astute clinician

may find suggestive evidence before

puberty,2.7 and even in the newborn. If oneis seeking it, Klinefelter’s syndrome can besuspected and definitively diagnosed yearsbefore obvious clinical manifestations occur.

Klinefelter’s syndrome is common enoughto warrant consideration by pediatricians inpractice. They should be aware of the clinicalphenomena, the best management of a childborn with the syndrome, and what geneticycounseling advice is appropriate.

If one is seeking it, Klinefelter’s syndromecan be suspected and definitively diagnosedyears before obvious clinicai manifestations

occur.

Potential clinical advantages of detectingKlinefelter’s syndrome at birth include bothearly counseling of the baby’s doctor andfamily, and early detection of the clinicalmanifestations.

Original Observations

Since May 1971, we have been screeningpractically all (99.7%) of the newborn malesover 28 weeks of gestation born at Sinai

Hospital of Baltimore for possible Xchromosome aneuploidy a.S.H.), and at-

tempts have been made by our Genetic

Counseling Clinic to offer genetic counseling(R.H.H.). These experiences have presentedus with the opportunity to try to create

interest in the very early diagnosis and

management of Klinefelter’s syndrome, andto study prospectively the reactions of anumber of pediatricians and parents to earlygenetic counseling.The principal X chromosome aneuploidy

to be found in the liveborn baby boy involvesan increase in the number of X chromo-

somes. The somatic cell nuclei in a normalmale have only one X chromosome. Thepresence of at least one X chromosome isessential for male viability.

Comparison between phenotypic sex andnuclear sex is used as a screening method toidentify the presence of X chromosome

aneuploidy. A discrepancy in the screeningtest suggests the presence of X chromosome

aneuploidy. When this is encountered, oneperforms a full chromosome analysis to

confirm the aneuploidy and to specificallyidentify the karyotype.

In the baby, phenotypic sex can be deter-mined by physical examination. Nuclearsex can be determined at birth by Barrbody (sex chromatin body) counts on amni-otic membrane epithelium cells; more than 3per cent cells having Barr bodies is taken asindicative of a so-called &dquo;female nuclear sex.&dquo; &dquo;

When a discrepancy is noted between

phenotypic sex and nuclear sex, the findingsare checked by buccal smear studies. Detailsof the method of determining nuclear sexhave been described elsewhere. 1,10-13

Normally the Barr body is found only witha female XX chromosomal constitution, notwith the XY male constitution. However,this chromatin body may be present in anapparent male who has an XXY or XXXYconstitution, a true hermaphrodite, and afemale with congenital adrenal hyperplasiawho has experienced complete virilization.Among 2,176 almost consecutively born

newborn males delivered between May 18,1971 and August 26, 1972, seven were

phenotypic males (0.32%) with &dquo;female nu-clear sex.&dquo; Each of these boy babies with a

&dquo;

discrepancy between phenotypic sex andnuclear sex was found by chromosome

analysis to have a 47,XXY karyotype.

Summary of Cases anti crf Reactionsto Genetic Counseling*

Case #1. J.R.P. Born June 23, 1971, two weeksafter full term, to a 24-year-old, unmarried,healthy, Mexican-American woman. Birth weightwas 2,495 g. The infant appeared a normal male

* Initial examinations were done by private or residentpediatricians. Fallt~w-up examinations, when per-formed, were done by R.H.H.

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583

on physical examination, except for one unde-scended testicle. Amniotic epithelium cells re-

vealed 98 per cent positive Barr bodies. In the

checkup, 35 per cent of the biaccal smear cellswere positive for Barr bodies. Karyoty pe provedto be 47,XXY. When re-examined at four monthsof age, the infant was normal appearing andnormally developed. Both testes were descendedbut unusually firm.The mother seemed pleased with the baby and

felt that he was normal. Both parents were

counseled concerning the nature and prognosis ofKlinefelter’s syndrome; they appeared uncon-

cerned about the diagnosis and were skeptical ofthe prediction of probable sterility. They politelyrejected further clinical follow-up of the babyregarding this clinically unapparent congenitalabnormality. This was not a private but a servicepatient. The pediatric resident involved in theinfant’s care was interested in the scientific andsocial aspects of the case, and had urged themother to attend the Genetic Counseling Clinic.

Case #2. C.E.M. Born August 28, 1971, at term,to a 19-year-old, married, healthy, black mother.The birth weight was 2,780 g. The infant seemednormal on physical examination except for small,soft testes, one of which was incompletely de-scended. The amniotic epithelium cells showed 100per cent positive Barr bodies. The buccal smearcells showed 17 per cent positive Barr bodies.Chromosomal karyotype was 47,XXY. On re-

examination at 13 months of age, both testes weredescended but were small and soft.

Because of external factors, this family was notseen for genetic counseling until the infant was 13months of age. When counseled concerning thenature and prognosis of Klinefelter’s syndrome,the parents received the information with consid-erable equanimity and indicated that despite theprognosis of probable sterility, the child appearedso normal that they were not concerned.The private pediatrician was relatively unin-

volved, as the mother expressed her intention ofchanging to a well-baby clinic. He did encouragefollow-up at the Genetic Counseling Clinic.

Case #3. B.B.M. Born September 27, 1971, twoweeks before full term, to a 43-year-old, married,healthy, white woman. At birth, the baby weighed2,501 g and was recognized as having congenitalheart disease. (Later the diagnosis of ventricularseptal defect was made.) The rest of the physicalexamination, including the genitalia, seemednormal. Amniotic epithelium cells were 99 percent positive for Barr bodies. Buccal smear cellswere 40 per cent positive for Barr bodies.Karyotype was 47,XXY.

Because of the cardiac disorder, it was decidedto defer discussion of the chromosomal abnormal-ity with the parents. This discussion was eventu-ally held by the private pediatrician. He reportedthat the family was so pleased that the baby’s

cardiac disease was only a small ventricular septaldefect with a good prognosis that the inapparentgenetic problem seemed insignificant to them.The private pediatrician mirrored the feelings

of the parents.Case #4. B.B.M. Born October 25, 1971, two

weeks before full term, to a 28-year-old, married,healthy, white mother with a history of eight yearsof involuntary infertility. At birth, the babyweighed 3,335 g, and was said to be normal onphysical examination. Amniotic epithelium cellswere 100 per cent positive for Barr bodies. Buccalsmear cells were 17 per cent positive for Barrbodies. Karyotype was 47,XXY. At one month ofage, the baby was seen in the Genetic CounselingClinic where several hemangiomas and a hairynevus were noted. The genitalia were deemednormal except for conspicuously small, firm,scrotal testes.

Comparison between phenotypic sex andnuclear sex is used as a screening methodto identify the presence of X chromosome

aneuploidy.

At approximately three months of age, the

parents were informed by the counseling physi-cian of the diagnosis of Klinefelter’s syndrome,and the nature and prognosis of the syndromewere described to them. They appeared to acceptthis with considerable equanimity and apparentsophistication, but shortly thereafter they ex-

pressed their concerns to a social worker. Themother’s attitude seemed to be one of denial ofthe diagnosis. The father’s attitude was charac-terized by disappointment in the prognosis ofprobable sterility. _

The parents and child were seen again whenthe baby was 15 months of age. The child

appeared developmentally and physically normal.The diagnosis of Klinefelter’s syndrome appearedwell accepted, though possibly underestimated atthis time. The parents were happily contemplat-ing the prospects of another pregnancy.The private pediatrician preferred to delegate

genetic counseling to one of us (R.H.H.).Case #5. B.B.H. Born on January 3, 1972, at

full term, to a 23-year-old, married, healthy,white woman. At birth, the baby weighed 2,975 gand was reported as normal on physical examina-tion. Amniotic epithelium cells were 99 per centpositive for Barr bodies. Buccal smear cells were12 per cent positive for Barr bodies. Karyotypewas 47,XXY.The private pediatrician did not permit the

patient to be seen in the Genetic CounselingClinic for counseling or follow-up. He indicatedthat he told the parents that the baby looked

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584

normal but was sterile and would need hormonesin the future. The chromosomal abnormality wasnot explained. He reported that the mother wasinitially emotionally upset by this news. Later, sheexpressed disbelief that this normal-looking babyhad a problem.

Case #6. B.B.K. Born March 21, 1972, at fullterm, to a 37-year-old, married but separated,white woman with a long history of psychiatricdisease. At birth, the baby weighed 3,210 g andwas deemed normal on physical examination.Amniotic epithelium cells were 95 per cent posi-tive for Barr bodies. Buccal smear cells were 15

per cent positive for Barr bodies. Karyotype was47,XXY.The mother was a very suspicious person, and

it was difficult to get a history from her. The

No evidence exists that the chromosomal)

nondisjunctional process which causesthis abnormality is more apt to repeat inany particular family than is the averagein the population of that geographic area.

private pediatrician preferred not to discuss theKlinefelter’s syndrome with her and indicatedthat no further attempts to get follow-up throughthe Genetics Counseling Clinic would be accepted.He later reported that he told the mother onlythat a test was done which showed that her hovwould be sex-hormone deficient and would needhormones in the future. He related that herreaction was one of seeming disinterest in the

baby’s nonapparent problem.Case #7. B.B.H. Born August 26, 1972, two

weeks past full term, to a 15-year-old, unmarried,white girl. At birth, the baby weighed 2,701 g.The infant seemed normal on physical examina-tion. Amniotic epithelium cells were 97 per centpositive for Barr bodies. Buccal smear cells were27 per cent positive for Barr bodies. Karyotypewas 47,XXY.The baby was made available for adoption. The

private pediatrician involved, who representedthe adoption agency, had no opportunity to

develop a patient-doctor relationship with this

young mother. Since the chromosomal nondis-junction which is responsible for Klinefelter’ssyndrome is thought not to be familial or likely torepeat any more often that its average incidencein the community, he decided not to discuss thisproblem with her. The adoption agency was

informed that the baby had Klinefelter’s syn-drome, and their decision was to consider thebaby adoptable. No counseling of the adoptiveparents was requested, and the infant is lost to

follow-up.The pediatrician pondered the propriety of

sanctioning adoption of a Klinefelter’s syndromebaby without adequate counseling of the adoptiveparents.

Discussion

The implications to genetic counseling oftelling a family and a pediatrician that anessentially normal looking baby may developthe problems associated with Klinefelter’s

syndrome are significant. The counselor orpediatrician is not always believed by theparents when they are told that a normal-appearing baby has or will develop an ab-normality. They are often more concernedwith the current status and problems thanwith potential future ones if the baby seemsnormal to them. The counseling physiciancan only describe the syndrome, and indicatethat some or all of it may develop in anyparticular patient. He must do this accu-

rately but lightly, as he does not want to

create undue anxiety in the parents yet doeswant to follow the baby.The pediatrician in his genetic counseling

role must consider:

1. Is the diagnosis certain?2. What problems can we be sure will

. develop?3. What shall I tell the family, and

when?4. What can be done for the baby?5. Will this syndrome reoccur in other

pregnancies?In the newborn we can be certain of the

diagnosis, but not of which portions of thesyndrome will develop. The specifics of what.to tell the family and when are not clear cut.Our policy has been to be forthright andhonest, but tactful. Exactly what can be donefor anyone with this syndrome depends onwhich manifestations appear, and at what

phase of their development they are recog-nized. Nothing can be done about the steril-ity except to apprise the patient of the fact atan appropriate age. For patients in whom agynecoid habitus develops, the careful andtimely use of androgens may be helpful.Anticipation of intellectual and behavioraldifficulties will allow the best opportunity foroptimal management.

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585

No evidence exists that the chromosomal

nondisjunctional process which causes this

abnormality is more apt to repeat in anyparticular family than is the average in the

population of that geographic area.Of our seven newborn infants found with

Klinefelter’s syndrome, only one family bothreceived and responded favorably to coun-seling (Case #4). In three other families,counseling attempts were more or lessthwarted by a negative parental response,and no long-term clinical follow-up is antici-pated. This was partly due to the naturalskepticism when a family is told that a

normal-looking baby has a disease. In two

families, the private pediatrician intercededin a way which prevented counseling by agenetic counselor. The seventh infant waslost to follow-up because of his intermediaryplacement with an adoption agency.Although the total number of cases here is

small, it appears that achieving long-termgenetic follow up for boys with Klinefelter’ssyndrome requires education of, and activesupport by, the pediatric community.Perhaps, stressing that subtle abnormalitiesof the genitalia such as undescended or

unusually hard or soft testicles can be foundat birth in some instances of Klinefelter’s

syndrome will engender interest by clini-cians.When suspicious of this syndrome, one

should order a buccal smear to identify thenuclear sex. If the nuclear findings are

those of a girl when the infant seems to bea boy, further chromosomal studies forKlinefelter’s syndrome are indicated. With afirm diagnosis made, the pediatrician shouldfollow this baby closely while making theparents aware of the nature of the disorder.

AcknowledgmentSpecial thanks are due Linda Jenne, Goldie Gershen,

Clara Hirsch, Sharonn Gittelsohn, M.S.W., Eileen Lesser,and the resident and nursing staffs of the Departments ofObstetrics and Pediatrics.

References

1. Caldwell, P. D., and Smith, D. W.: The XXY(Klinefelter’s) syndrome in childhood: detectionand treatment. J. Pediatr 80(2): 250, 1972.

2. Ferguson-Smith, M. A.: Chromatin-positiveKlinefelter’s syndrome (primary microrchidism)in a mental-deficiency hospital. Lancet 1: 928,1958.

3. —: The prepubertal testicular lesion in chroma-tin-positive Klinefelter’s syndrome (primary mi-crorchidism) as seen in mentally handicappedchildren. Lancet 1: 219, 1959.

4. Froland, A.: Klinefelter’s syndrome. Clinical, en-

docrinological and cytogenetic studies. DanishMed. Bull. 16: 1, 1969.

5. Klinefelter, H. F., Jr., Reifenstin, E. C., Jr., andAlbright, F.: Syndrome characterized bygynecomastia, aspermatogenesis without

A-Leydigism and increased excretion of FSH. J.Clin. Endocrinol. Metab. 2: 615, 1942.

6. Laron, Z., and Hochman, I. H.: Small testes in

prepubertal boys with Klinefelter’s syndrome. J.Clin. Endocrinol. Metab. 32: 671, 1971.

7. Nielsen, J., Sorensen, A., Theilgaard, A., Froland,A., and Johnsen, S. G.: A psychiatric-psychologicalstudy of 50 severely hypogonadal male patients,including 31 with Klinefelter’s syndrome, 47XXY. Acta Jutlandica, 41 (3), University ofAarhus, Copenhagen: Munksgaard, 1967.

8. Tanner, J. M., Prader, A., Habich, H., and

Ferguson-Smith, M. A.: Genes on the Y chromo-some influencing the rate of maturation in man:skeletal age studies in children with Klinefelter’s

(XXY) and Turner’s (XO) syndromes. Lancet 2:141, 1959.

9. Harris, J. S., and Robinson, A.: X chromosomeabnormalities and the obstetrician. Am. J. Obstet.Gynec. 109 (4): 574, 1971.

10. Culling, C. F. A.: Staining Affinities and Cytochem-ical Properties of the Sex Chromatin. In Moore,K. L., Ed: The Sex Chromatin. Philadelphia, W.B. Saunders Company, 1966, p. 91.

11. Klinger, H.P.: The sex chromatin in fetal andmaternal portions of the human placenta. ActaAnat. (Basel) 30: 371, 1957.

12. Klinger, H. P., and Ludwig, K. S.: A universal stainfor the sex chromatin body. Stain Technol. 32:235, 1957.

13. Robinson, A., and Puck, T. T.: Studies on

Chromosomal nondisjunction in man. II. Am. J.Hum. Genet. 19: 112, 1967.

Editor’s Comment

Two conclusions can be reached from the data

presented in this article. One, Klinefelter’s syn-drome can be identified at birth and two, theinformation gleaned from that screening will notbe accepted by the parents and possibly, in

addition, by the pediatrician!The primary advantage of knowing about the

existence of Klinefelter’s syndrome, according tothe authors, is to provide more optimum man-agement of the disorder. Since these patients havea normal life expectancy but &dquo;very chaotic andunpredictable life patterns which work againstany therapeutic or rehabilitative efforts,&dquo;’ it maybe valuable to determine whether or not earlyknowledge about the condition can affect be-

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