February, 1972

250 T h e Journal of P E D I A T R I C S

childhood: Detection and treatment

Detection oJ the X X Y chromosomal imbalance, the genetic cause of X-chromatin-positive

Klinefelter's syndrome, has generally been delayed until the postadolescent period.
Several clinical [eatures may assist in the ascertainment o[ patients during the
childhood period. These boys often have school and~or behavioral problems in association
with borderline dull mentality and tend to have a slim build with relatively long lower
extremities and somewhat small external genitals. A buccal smear can be utilized for
screening purposes. IJ X-chromatin positive, then chromosome studies are indicated to
rule out the presence o[ mosaicism and to define the exact nature of the chromosomal
abnormality. Age-appropriate physiologic testosterone replacement therapy is then
recommended in order to provide a more normal adolescent growth and development
and to prevent most o[ the characteristic [eatures of the older patient with Kline[elter's
syndrome.

Peter D. Caldwell, M.D., and David W. Smith, M.D., Seattle, Wash.

A B O U T 1.7 per 1,000 newborn male in- 3 cases of the X X Y syndrome in childhood
fants are X-chromatin positive, 1 many of and to indicate some clinical criteria that
whom will have problems relative to the may allow for the detection of the X X Y im-
X X Y syndrome. Although this chromosomal balance prior to adolescence. In addition,
imbalance is second in frequency only to some comments will be made on pertinent
Down's syndrome, the diagnosis of the X X Y cytogenetic studies to confirm the diagnosis,
syndrome is rarely made until the period of and our approach to testosterone replace-
expected pubescence or usually later. Since ment therapy for the adolescent X X Y in-
these individuals generally do not produce dividual will be described.
adequate androgen, it would be desirable to
CASE REPORTS
detect them during childhood in order to
anticipate testosterone substitution therapy Case 1. This 9-year-old boy (Fig. 1, A) was
and thus bring about more normal growth seen because he expressed concern about his small
and maturation through the adolescent peri- genitals. There had been no prior health or
od. It is the purpose of this paper to report behavioral problems. His school performance
had been satisfactory. Physical examination
showed him to be a tall, slim child with relatively
From the Dysmorphology Unit, Department long legs. Height was 112 cm. with an upper-to-
o[ Pediatrics, University of Washington School lower segment ratio of 0.87. The testes measured
of Medicine.
Supported by a grant [rom the Children's 1.8 x I.I cm. and were normal in consistency.
Bureau. The penis appeared small, measuring 4.5 x 1.3
VoI. 80, No. 2, pp. 250-258
Volume 80 Kline[elter's syndrome 251
Number2

Fig. 1. A, Case 1 at age 9 years. B, Case 3 at age 12 years. Note the slim build with long
extremities as well as the small external genitals.

cm. A buccal smear was obtained which showed was 96. The child was subsequently seen in our
27 per cent of the cells to be X-chromatin posi- clinic for further evaluation and counseling.
tive. A psychological evaluation revealed the Height was 141 cm. with an upper-to-lowei" seg-
full-scale I.Q. (Wechsler Intelligence Scale for ment ratio of 0.92; weight was 36.7 Kg. The
Children [WISC]) to be 107. A testicular biopsy testes measured 1.4 cm. in length. At age 12
was performed, and the results are shown in height was 146 cm. There was a mild change in
Fig. 4. body contour with an accumulation of adipose
Case 2. The diagnosis of the XXY syndrome tissue around the waist and hips. Examination
was made in this 10%-year-old boy by his family of the genitals revealed a phallus measuring 4.5
physician, who had evaluated him for the com- x 1.5 cm. and testicles 1.2 cm. in length with no
plaints of easy fatigability a n d poor school per- clinical evidence of androgen effect. A regimen
formance during the previous year. The testes of testosterone cyclopentylproprionate (Depo-
were noted to be unusually small. He was X- Testosterone, The Upjohn Co.) in gradually in-
ehromatin positive, and chromosome studies on creasing dosage was instituted as outlined in the
cultured leukocytes revealed XXY without evi- discussion.
dence of mosaicism. His full-scale I.Q. (WISC) Case 3. This 12-year-old boy (Fig. t, B) was
252 Caldwell and Smith The Journal of Pediatrics
February 1972

11.15
1.10
1.05 Mean values)

.~ L.oo
113
0
E 0.95 0
9 0 0
0.90 0 0 0

0
0.85
0 0 0
"- 0 . 8 0
0 0
~" 0 . 7 5 -

~. 0 . 7 0

0,65- 0
9 Patients 1,2,5
0.60 0 0 Other patients

0.55
6
' ; ' ,b' ,i ' '
14
',;
Age in years
Fig. 2. Diminished upper-to-lower segment ratio in boys with the XXY syndrome in the present
patients and others from the literatureY, ,-12 Normal standards from Wilkins, L.: The diagnosis
and treatment of endocrine disorders in childhood and adolescence, Springfield, Ill., 1965,
Charles C Thomas, Publisher.

evaluated because of shortness of stature and mass screening in the newborn period, has
poor school performance. He had been considered been buccal smear for X chromatin and
a normal child until learning difficulties de- chromosomal examination o f boys with dull
veloped in school. There was a family history of mentality a n d / o r school or behavioral diffi-
short stature, but the patient was actually taller
culties. Because of sampling bias the inci-
than his siblings had been at a comparable age.
dence of significant mental deficiency among
Upon examination he was found to be a some-
what shy, slim youngster whose height was 139 boys with the X X Y syndrome is uncertain.
era. with an upper-to-lower segment ratio of General surveys of males in institutions for
0.83. The testicles measured 1.5 cm. in length. the mentally defective have indicated a much
The penis was 5.5 by 2 cm. There was mild higher frequency of X-chromatin-positive
limitation in full supination of the elbow. Psycho- males in those with an I.Q. above 50 than
logical testing disclosed a full-scale I.Q. (WISC) a m o n g the more severely mentally deficient
of 71. An X-chromatin-positive buccal smear patients5 Screening of boys in schools for
was demonstrated, and chromosome studies on the educationally subnormal (I.Q. 50 or
cultured leukocytes revealed a straight XXY greater) has yielded a combined frequency
complement. A program of increasing testosterone
of 7.4 X-chromatin-positive individuals per
replacement therapy was started.
1,000 males, a an incidence which is 4 to 5
times that obtained in newborn male sur-
DISCUSSION
veys. An even higher incidence is found when
Clinical clues to the detection of the X X Y ascertainment is based solely on problems
syndrome in childhood. T h r e e general areas of a behavioral or psychiatric nature. I n a
appear to offer clinical clues to the detection survey of 620 boys who entered the Depart-
of the X X Y syndrome in childhood. m e n t of Child and Youth Psychiatry in U p p -
Psyehosoeial problems. T h e most frequent sala, Annell and associates 2 found 10 to be
means of ascertainment of these individuals, X-chromatin positive (a frequency of 16
other than utilization of the buccal smear for per 1,000) and of these the majority had
Volume 80 Kline[elter's syndrome 253
Number 2

190 Pete
0 84th
t ,j~O Median
70] /'l::~b~ 16,,

.
'3~ 1
~: I 1 0 ~ -- Patients1,2.3
90 ['1 ,nei tap . . . . . . , , 0 ,rehOt , , is
6 8 I0 12 14 16 18
Age in years
Fig. 3. Tendency toward increased stature in boys with the XXY syndrome. Normative data
is from the University of Iowa growth chart with height measurements from the present
patients and those from the literature. 2, s-13, 1~

I.Q.'s in the lower range of normal.

The presence of the additional X chromo-
some appears to be at least partially responsi-
ble for a tendency toward the development of
personality and behavioral disorders. Such a
conclusion was reached by Nielsen and co-
workers 3 based on their observations of psy-
chopatholog3r in 50 adult individuals ascer-
tained because of primary hypogonadism and
infertility. The problem of hypogonadism was
similar in these patients, but the frequency
of psychopathologic symptoms such as im-
maturity, insecurity, and boastful and asser- Fig. 4. Testicular biopsy from Case 1 at age 9
tive behavior was significantly greater in the years showing decreased cellularity of the tubules
34 men who were found to have the X X Y with apparent absence of germ cells. X-chromatin
masses are also evident. (Bouin's fixative, Masson's
syndrome as compared to the other 16 who stain. Original magnification x650.)
had no chromosomal abnormality. Several
other reports have reviewed the adult psy- Body habitus. Tanner and associates s have
chopathologic manifestations of the X X Y previously noted that relatively long legs are
syndrome,4-6 whereas observations in child- evident even before adolescence in individ-
hood are limited. Problems noted in child- uals with the X X Y syndrome. As is evident
hood are often initiated or aggravated by in Fig. 1, both boys appear to have relatively
school entrance. These include such aberra- long limbs. These skeletal proportions are
tions as nervousness, excessive shyness, im- reflected in a low upper-to-lower segment
maturity, lack of self-confidence, intermittent ratio as depicted in Fig. 2. Stature in general
agressiveness, and antisocial actsY, ~ Cases 2 tends to be increased for age as illustrated
and 3 are rather typical examples of boys in Fig. 3. In addition, these boys in general
who have appeared reasonably normal and tend to be slim and underweight for length.
then begin to encounter early school difficulty Varying habitus in terms of height and weight
either in terms of learning or adjustment. in accordance with genetic background can
Such situations, especially in the presence be expected as seen in Case 3 whose relative
of relatively dull mentality, should lead to shortness of stature was compatible with the
the consideration of the X X Y syndrome as family pattern.
a possibility. External genitals. The basic testicular de-
254 CaldwelI and Smith The Journal of Pediatrics
February 1972

5.0-
9 Patients 1,2,8r
00fher patients ~" -20
/

4.0-

.~.
3.0-
5 ,u
0
. . 0 ~ / e ' Se'S/0
/ 00 00 0 0

. . . . . . . . . . . . . . . . . . . . . . . . . _ _

2.o-
aL o 1 o o
oo o o o o
o o o o o
o
t.0-

4 ' 6 ' 8 ' 1'(3 ' 1'2 ' 1'4 ' 16

Age in yeors
Fig. 5. Testis size of the present patients and additional XXY patients from the litera-
ture9, 10, 12-14,1~ with representative normal testicular growth curves,s6 Note the tendency of
testis size to be in the small to low-normal range during childhood with subsequent lack of
normal enlargement through adolescence.

fect which has been noted in the X X Y syn- cellular unresponsiveness in terms of phallic
drome in infancy and childhood 14-16 is a enlargement in those X X Y individuals
reduction in the number of germinal cells treated with testosterone. T h e degree of in-
and hence in tubular diameter as shown in adequacy of the development of the external
Fig. 4. T h e testes tend to be small, 17 over- genitals can be more than the small size of
lapping into the normal range for age as the phallus. For example, an occasional in-
depicted in Fig. 5. Gonadotrophin stimula- dividual with the X X Y syndrome has incom-
tion at adolescence does not result in testicu- plete development to the point of having
lar enlargement to tile normal extent since hypospadias. Cryptorchidism a n d / o r incom-
the germinal elements, reduced in number, plete formation of the external genitals,
do not normally mature and the patients especially hypospadias, has been reported in
are generally infertile. If patients do not re- X-chromatin-positive infants as well as in
ceive testosterone replacement therapy at older boys who were found to have the X X Y
adolescence, the testicular histology usually chromosome complement2, 20, 21, 23, ~4
shows hyalinization and fibrosis within the Therefore, in the clinical evaluation of the
tubules and islands of hyperplastic Leydig external genitals, small testes and a small or
cells which are presumed to be functionally incompletely developed phallus are of value
inadequate, since not enough testosterone for as potential clues to the detection of tile
normal virilization is produced. X X Y syndrome. Case 1, as well as others, ~, 2~
There is also a tendency for the phallus have been detected solely on this basis.
to be smaller than average in the X X Y in- Cytogenetic diagnosis of the X X Y syn-
dividuM prior to adolescence, as indicated drome and variants. Given any of the fore-
in Fig. 6. This feature may represent inade- going diagostic clues, a buccal smear can be
quate Leydig cell testosterone production utilized as a general screening technique for
during the stage of fetal life when the de- the detection of the X X Y syndrome. For
velopment of the external genitals is andro- those males who are X-chromatin positive
gen dependent. There is no indication of end (indicative of the presence of a second X
Volume 80 Klinefelter's syndrome 255
Number 2

I 6- Percentile
A Patients 1, 2, 3 9"
14 0 Other patients / 90th

~]20 / / Median
j/7o
"~I

o o o

0 ,
0 IO 16
Age in years
Fig. 6. Penile length in boys with the XXY syndrome with data from the present patients and
untreated individuals from the literature. 9, 1~-1s, lz, 19, z0 Measurement is of the fully stretched
phallus from the pubopenile skin junction to the tip of the glans. Normative data is from
Schonfeld. is

chromosome), routine chromosome studies nosis for viriIization and fertility. The X Y /
are recommended for the following rea- X X Y male should be evaluated at adoles-
sons. cence for the degree of testosterone produc-
Mosafcism. Of 23 X-chromatin-positive tion and virilization in order to determine
newborn males for whom chromosome studies whether testosterone replacement therapy is
were done, 22 per cent had X Y / X X Y mo- indicated; he should also be evaluated for
saicism? It is not possible to predict to what sperm production as an adult before infer-
extent these individuals will manifest features tility is implied.
of the X X Y syndrome. For example, only XXYY. Preadolescent boys with the
12 per cent of X-chmmatin-positive males X X Y Y karyotype have been identified29-a~;
ascertained because of mental deficiency were they have shown features which are quite
found to have mosaicism? Studies in adult similar to those with the X X Y syndrome.
X Y / X X Y mosaic patients 2~ 27 have indi- They may have an unusual dermatoglyphic
cated that features of the X X Y syndrome pattern sa which could suggest the X X Y Y
are present but generally in decreased fre- chromosome situation. A buccal smear for
quency and severity in these mosaic indi- X chromatin would not distinguish the
viduals. Chromosome studies are indicated X X Y Y from the X X Y individual; hence
because the frequency of X-chromatin-posi- chromosome studies are indicated.
tive cells in buccal smears does not necessar- X X X Y and X X X X Y . These unusual vari-
ily correlate well with the degree of rno- ants should be considered in the X-chro-
saicism in X Y / X X Y individuals. The im- matin-positive boy. Clinically, such indi-
portance of determining whether an X- viduals are more likely than the X X Y male
chromatin-positive boy is mosaic for X Y / to be mentally retarded and to have short-
X X Y relates to the potentially better prog- ness of stature, unusual facies, and elbow
256 CaldweIl and Smith The Journal ot Pediatrics
February 1972

Table I. Features which can be of value in dysplasia. Some of their buccal cells show
the clinical detection of the X X Y syndrome more than one X-chromatin mass, indicating
the presence of more than two X chromo-
Features I Child I Adult
somes in their cells; chromosome studies
Psycho- Dull mentality, Increased psycho- show 48 and 49 chromosomes, respectively,
social school and/or pathology, dis-
behavioral prob- turbed body for the X X X Y and X X X X Y constitutions.
lems image Testosterone replacement therapy. O n e of
Testes Small size second- Small size with the major objectives in ascertaining the X X Y
ary to decreased hyalinization and individual prior to the age of adolescence is
germ cell mass fibrosis to prevent those features of Klinefelter's syn-
Incomplete virili- drome which are predominantly due to aber-
zation, gyneco- rant and inadequate testicular function. As
mastia
shown in Fig. 7 and Table I, the features
Phallus Small size possibly Small size second- which Klinefelter and associates s4 originally
secondary to in- ary to inade-
adequate andro- quate testoste- described are the eventual result of the X X Y
gen rone production genetic imbalance in the postadolescent pa-
Body Long legs with Eunuchoid habi- tient. Age-appropriate physiologic replace-
habitus decreased upper- ms, increased ment therapy with testosterone should insure
to-lower segment truncal adiposity more normative adolescent growth and de-
ratio and decreased
Slim build with muscle mass velopment and hopefully prevent gyneco-
decreased weight mastia and other features of untreated hypo-
for height gonadism. Such treatment is especially im-

Fig. 7. A, Nine-year-old child. B, Sixteen-year-old adolescent. C, Twenty-one-year-old adult.

Volume 80 Klinefelter's syndrome 257
Number 2

portant in an individual who already has X-chromatin-positive boys in order to detect

some limitation in his ability to compete and the presence of mosaicism or other X X Y
adjust with his peers. variants. Diagnosis prior to adolescence is
T h e onset of adolescence is normally warranted in order to provide physiologic
brought about by a gradual 20-fold increase testosterone replacement therapy in the hope
in testosterone production from the prepu- of obtaining more normal adolescent growth
bertal to the adult level. Testosterone pro- and development and more appropriate social
duction in the untreated X X Y patient usu- adaptation.
ally increases somewhat through adolescence
but is inadequate to bring about normal REFERENCES
virilization. For example in one study, plasma 1. Court Brown, W, M.: Sex chromosome aneu.
testosterone values in X X Y men average 0.28 ploidy in man and its frequency, with special
?g per 100 ml. compared to a normal aver- reference to mental subnormality and criminal
behavior; Int. Rev. Exp. Pathol. 7: 31, 1969.
age of 0.67 t~g per 100 ml. 27 2. Annell, A. L., Gustavson, K. H., and Ten-
O u r present practice is to initiate testos- stare, J.: Symptomatology in school boys with
terone replacement therapy at 11 to 12 years positive sex chromatin (The Klinefelter syn-
drome), Acta Psychiatr. Scand. 46: 71, 1970.
of age and gradually increase the dose to full 3. Nielsen, J., Sorensen, A., Theilgaard, A., Fro-
adult levels by 15 to 17 years. For example, land, A., and Johnsen, S. G.: A psychiatric-
in Case 2 therapy with Depo-Testosterone psychological study of 50 severely hypogo-
nadal male patients, including 33 with Kline-
was instituted with a dose of 50 mg. intra- felter's syndrome, 47 XXY, Acta Jutlandica
muscularly every three weeks; the dose was 41, No. 3, University of Aarhus, Copenhagen:
increased to 100 rag. after 6 months, and Munksgaard, 1967.
4. Hoaken, P. C. S., Clarke, M., and Breslin, M.:
subsequent increases of 50 mg. are planned Psychopathology of Klinefeher's syndrome,
at 9 m o n t h intervals until a maintenance Psychosom. Med. 26: 207, 1964.
adult dosage of 250 rag. every 3 weeks is 5. Pasqualini, R. Q., Vidal, G., and Bur, G. E.:
Psychopathology of Klinefelter's syndrome,
reached. Oral agents are not recommended Lancet 2: 164, 1957.
at this time because of less predictable ab- 6. Kvale, J. N., and Fishman, J. R.: The psycho-
sorption and potential hepatic toxicity. There social aspects of Klinefelter's syndrome, J. A.
M. A. 193: 97, 1965.
may be some concern regarding testosterone 7. Louhivvori, K., and Jakobson, T.: Prepubertal
therapy in a boy with dull mentality a n d / o r Klinefeher's syndrome. Child psychiatric as-
behavioral problems. However, Myhre and pects illustrated by two case reports, Ann.
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associates 12 noted general improvement in be-
8. Tanner, J. M., Prader, A., Habich, H., and
havior and work performance in retarded Ferguson-Smith, M. A.: Genes on the Y
adolescent and young adult X X Y Patients chromosome influencing the rate of matura-
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O u r current policy is to provide all X X Y syndromes, Lancet 2: 141, 1959.
boys with at least a trim of testosterone re- 9. Jackson, J. F., and Montalvo, J. M.: Hypo-
placement therapy at the appropriate dosage spadias in Klinefeher's syndrome, J.' Urol.
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11. Prader, A.: Die Klinik der tt~iufigsten Chro-
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H. R., Thuline, H. C., and KelIey, V. C.:
hood are reported. Clues for early clinical The effects of testosterone treatment in KHne-
detection include : (1) dull mentality a n d / felter's syndrome, J. P~DIATR. 76: 267, 1970.
or school and behavioral problems, (2) al- 13. Bunge, R. C., and Bradbury, J. T.: Ten year
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and slim build, and (3) small testes and 14. Ferguson-Smith, M. A.: The prepub.ertal tes-
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felter's syndrome as seen in mentally handi-
Chromosome studies are indicated in all capped children, Lancet 1: 219, 1959.
258 Caldwell and Smith The Journal of Pediatrics
February 1972

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Martin-Du Pan, R.: Chromatin positive Kline- Philadelphia, 1966, W. B. Saunders Company.
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spermatogonial deficiency at 3, 4 and 12 R. W.: Klinefelter's syndrome and its variants:
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25. Lawrence, R., and Yuceoglu, A. M.: Seminif- the peripheral plasma of prepubertal children
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syndrome in a 10 month old child, Am. J. 36. Laron, Z., and Zilka, E.: Compensatory hyper-
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felter's syndrome and mental deficiency, in