American Journal of Medical Genetics 27:189-194 (1987)

Brief Clinical Report: Trisomy Xq in a Male: The lsochromosome X Klinefelter Syndrome

Michael A. Donlan, Cynthia R. Dolan, Michael J. Metcalf, Cynthia M. Bradley, and Darrell Salk

Inland Empire Genetics Counseling Service, Spokane (M.A. D., C. R. D), private practice, Spokane (M. J. M.), Cytogenetics Laboratory, Children’s Hospital and Medical Center, Seattle (C. M. 8., D. S), and Departments of Pathology and Pediatrics, University of Washington, Seattle (0. S.), Washington

We report on a male with trisomy Xq resulting from an isochromosome Xq which is preferentially inactivated: 47,XY, +i(Xq). Six previous cases have been re- ported. These patients are similar to patients with classical Klinefelter syndrome (47,XXY) in that they have infertility, decreased masculinization, gynecomastia, and elevated luteinizing hormone (LH) and follide stimulating hormone (FSH) levels. They may differ in having average intelligence and normal to short stature. These findings indicate that extra copies of the long arm of X have phenotypic expression, even though activated only in early development.

Key words: Klinefelter syndrome, trisomy Xq, isochromosome Xq, aneuploidy syndrome

INTRODUCTION

We wish to report a case of an unusual chromosome rearrangement which we are designating “Isochromosome X Klinefelter syndrome,” with a review of the literature.

CLINICAL REPORT

and gynecomastia. Family history was negative for mental retardation or infertility. M.B. was referred to our clinic at age 17 years for evaluation of short stature

Received for publication June 26, 1986; revision received October 6, 1986.

Address reprint requests to Dr. Michael A. Donlan, Inland Empire Genetics Counseling Service, West 800 Fifth Avenue, P.O. Box 248, Spokane, WA 99210-0248.

0 1987 Alan R. Liss, Inc.

190 Donlan et a1

M.B. was born at term after an uncomplicated pregnancy and delivery to a then 27-year-old, gravida 5 , para 3, sab 2 mother. The mother’s height was 160 cm (30th centile). His father was, at that time, 33 years old and had a height of 188 cm (> 95th centile). M.B.’s birth weight was 3,757 g and length at birth was 52 cm.

A right hydrocoelectomy was performed at age 2 years and he had meningitis at 4 1/2 years from which he recovered without apparent sequelae.

Examination at age 17 years showed a pleasant, cooperative young man whose height was 160 cm (< 3rd centile) and whose weight was 60 kg (25th centile). Although his general appearance was that of a normal male, he had some eunuchoid features with span (165 cm) greater than height (160 cm), lower body segment (85 cm) greater than upper body segment (75 cm) (L/U ratio Ll), and gynecomastia (palpable breast tissue 10 cm in diameter). Both testes were descended but were soft and small (length < 1 cm, volume < 2 cc). He was in Tanner Stage 111 pubertal development; facial hair had not yet required shaving. Dermatoglyphics on the right hand showed 3 ulnar loops, a whorl, and an arch and on the left hand, 3 ulnar loops and 2 whorls. The triradii were normally placed.

Subsequent to his initial evaluation, he has had a satisfactory reduction mam- moplasty and has been treated with replacement testosterone.

LABORATORY Endocrine. Twenty-four hr excretion of urinary 17-keto steroids, T-4, thyroid

stimulating hormone (TSH) , radiographic bone age study, and skull radiographs were normal.

Plasma testosterone levels were 232 ng/100 ml and 285 ng/100 ml (normal: 300-1,200 ng/100 ml). Serum FSH was 62 miu/ml (normal: 4-25 miu/ml). Serum LH was 51 miu/ml and 45 miu/ml (normal: 7-24 miu/ml). Plasma estradiol was under 12 pg/ml (normal: 12-34 pg/ml).

Cytogenetics. Chromosome analysis of peripheral blood lymphocytes and cul- tured skin fibroblasts were initially performed at 17 years of age. All 26 lymphocyte metaphases analyzed by G-, R-, and C-banding and 31 fibroblast metaphases analyzed by R-banding revealed a male karyotype with an extra isochromosome for the long arm of X: 47,XY, + i(Xq). Parental chromosomes were normal.

Repeat analysis of the patient’s lymphocytes at 23 years of age confirmed these findings in 33 metaphases studies by R- and G-banding (Fig. 1). BrdU-replication analysis (B-pulse) was performed using a modification of the technique employing Hoechst 33258 dye, overnight exposure to fluorescent light, and Giemsa staining [Latt et al, 1976; Camargo and Cervenka, 19841. (This technique results in a modified R-banding pattern with lightly stained late-replicating regions.) Among 50 cells scored for the replication pattern of the X chromosomes, the i (Xq) was late- replicating in all, suggesting that the abnormal X chromosome is preferentially inactivated (Fig. 2).

DISCUSSION

The first report of which we are aware of a 47,XY, +i(Xq) male was made by Zang et a1 [1969]. Five other cases have been reported [Gardiner and Brown, 1978; Kalousek et al, 1978; McDermott, 1978; Ponzio, 1980; Trunca et al, 19791. The clinical and laboratory data on these cases are summarized in Tables I and I1 along with the features of the 47,XXY Klinefelter syndrome.

Isochrornosome X Klinefelter Syndrome 191

Fig. 1. Partial G-banded karyotype of the patient showing (left to right) normal Y, normal X, isochromosome Xq.

Fig. 2. Partial metaphase spread from a B-pulsed lymphocyte culture showing late replicating i (Xq) (large arrow). The normal X and Y chromosomes are indicated by small arrows.

The 47,XY, +i(Xq) and 47,XXY patients all have infertility, decreased mascu- linization, gynecomastia and elevated LH and FSH levels. Several differences were noted, however: the 47,XY, +i(Xq) patients are reported to have average intelligence and normal to short stature (mean 166 cm, > ,loth centile).

In 47,XY,+i(Xq) there are two additional long arms of an X chromosome without additional short arm material: thus trisomy Xq in a male. In our patient, the abnormal X chromosome is preferentially inactivated and does not contain any of the Xp region that excapes inactivation in normal females. Thus, the Klinefelter syndrome can be produced in a Y-bearing person with only a single Xp but with extra Xq material. This has previously been reported for an individual with one Xp and two Xqs resulting from an unbalanced translocation [Pallister and Opitz, 19781.

Women with 45,X compared with 46,X,i(Xq) Turner syndrome are clinically indistinguishable. This observation suggests that the short arm of X must be present to prevent the development of the Turner phenotype, possibly because Xp partially

TABL

E

I.

Clin

ical

Feat

ures

Aut

hor

Zang

Gar

dine

r

Ponz

io

Kal

ouse

k

Trun

ca

Cla

ssic

al

Clin

ical

et

a1

et

a1

et

a1

et

a1

McD

erm

ott

et

al

Pres

ent

Klin

efel

ter

feat

ures

[ 19

691

[ 19

781

[198

0]

[ 19

781

[197

8]

[ 19

791

repo

rt

synd

rom

e

IQ

Nor

mal

Ave

rage

Infe

rtilit

y

Yes

Yes

Age

(yea

rs)

44

36

Hei

ght

176c

m

164.

5

(50%

)

cm

Span

W

eigh

t Fa

cial

hair

(nl:

177

cm)

Pubi

c

hair

Gyn

eco-

m

astia

Te

stes

si

ze

Sper

mat

o-

gene

sis

Phal

lus

182

cm

84

kg

Spar

se

NIR

Sl

ight

Sm

all

NIR

N

orm

al

(<

5%

)

NIR

N

IR

Nor

mal

N

orm

al

mal

e N

one

(2

vol

ea)

AZO

O-

sper

mia

N

orm

al

Ave

rage

Nor

mal

Yes

Yes

33

24

168

cm

166.

4

cm

(10%

)

(5%

)

168

crn

180.

9

cm

63

kg

77.7

kg

NIR

Abs

ent

Tann

er

Nor

mal

Bila

tera

l

NIR

IV

Smal

l

1 cm

1 x 0.8

X

0.8

AZO

O-

AZO

O-

sper

mia

sper

mia

Tann

er

Smal

l

NIR

Y

es

29

163

cm

(<

5%)

167

cm

52.7

kg

NIR

N

IR

NIR

Sm

all

(2

in

vol)

Azo

o-

sper

nia

NIR

NIR

Ave

rage

NIR

?

32

17

NIR

160

cm

(<

5%)

NIR

165

cm

NIR

60

kg

Spar

se

Non

e

Fem

ale

Tann

er

patte

rn

11-11

1

Mild

Bila

tera

l

Hyp

o-

<

2cc

plas

tic

in

vol

N/R

?

Nor

mal

5cm

25%

MR

Yes

M

ean -

178.

9

cm

(65

%)

60%

With

in

3 cm

heig

ht

-

Scan

ty

to

abse

nt

Nor

mal

am

ount

pu

berty

50

%

post

<

2cm

A

bsen

t N

orm

al

IV

5x

2

to

shor

t

NIR

,

Not

repo

rted.

?, Not

Kno

wn.

TABL

E

11.

Labo

rato

ry

Stud

ies

Aut

hor

Zang

Gar

dine

r

Ponz

io

Kal

ouse

k

Trun

ca

Cla

ssic

al

Labo

rato

ry

et al et

al

et

al et al

McD

erm

ott

et a1

Pres

ent

Klin

efel

ter

study

[ 19

691

[ 19

781

[198

01

[197

81

[197

81

1197

91

repo

rt

synd

rom

e

Tes

tos-

NIR

1

1

1

1

1

Low

norm

al

tero

ne

Seru

m

1.1

mg/

130

232

ng/m

l

to

norm

al

5.9

nmol

ll

rnl

275-

1200

(300

-

1200

)

(8.5

-27.

5)

FSH

NIR

t t t t t t

Seru

m

70

62

miu

/ml

28.0

U/1

(5-3

0)

(4-2

5)

( 1-61

LH

N/R

t t t t t t

Ser

um

10.4

Seru

m

33.0

U/1

(2-1

0)

51

miu

/ml

(1-7

)

(7-2

4)

seru

m

12

pg

/d

(12-

34)

Urin

ary

t

gona

do-

15

HC

G

trop

ins

12

17

(4-8

) +i

(Xq)

+i(X

q)

+

i(Xq)

+i(X

q)

+i(X

q)

+i(X

q)

+i(X

q)

Kar

yoty

pe

47,

XY

,

47,

XY

,

47,

XY

,

47,

XY

,

47,X

Y,

47,

XY

,

47,X

Y,

47,

XX

Y

N/R

,

Not

repo

rted

.

194 Donlan et al

escapes inactivation [Therman et al, 1976; Therman et al, 19791 or because of its effect during early development before inactivation occurs. It appears that extra Xq material has relatively little phenotypic effect in women with 46,X,i(Xq). The occur- rence of the Klinefelter phenotype when extra Xq material is present in a male, however, indicates that Xq cannot be considered phenotypically inert, even though it is inactivated in later development.

Due to the limited number of reported cases of 47,XY,+i(Xq) males, it is probable that the full clinical spectrum has not yet been appreciated. Nevertheless, in the cases reported here there is a suggestion of some clinical differences between these men and 47,XXY Klinefelter syndrome patients, most noticeably the reports of “normal intelligence” and short stature. Although preliminary, the information may be of value when counseling families in which this chromosome rearrangement is detected prenatally.

ACKNOWLEDGMENTS

The assistance of Dr. Horace Thuline (Washington State Cytogenetics Labora- tory) and Dr. Thomas Nonvood (University of Washington Cytogenetics Laboratory) in the initial work-up of this patient is greatly appreciated. We would also like to thank Kara Campbell for her secretarial assistance and Dr. John Opitz for his helpful comments and review of the manuscript.

REFERENCES

Camargo M, Cervenka J (1984): DNA replication and inactivation patterns in structural abnormality of sex chromosomes. I. X-A translocations, rings, fragments, isochromosomes, and pseudoisodicen- trics. Hum Genet 67:3747.

Gardiner A, Brown MM, Gray JE (1978): Unusual chromosomal variant in Klinefelter’s syndrome. Br Med J 2: 1123.

Kalousek D, Cushman Biddle CJ, Rudner M, Arronet GH, Fraser FH (1978): 47,X,i(Xq),Y karyotype in Klinefelter’s syndrome. Hum Genet 43: 107-110.

Latt SA, Huntington FW, Gerald PS (1976): BrdU-33258 Hoechst analysis of DNA replication in human lymphocytes with supernumerary or structurally abnormal X chromosomes. Chromosoma 57: 135- 153.

McDermott A (1978): Personal communication. Pallister PD, Opitz JM (1978): The KOP translocation. In Summitt RL, Bergsma D (eds): “Sex

Differentiation and Chromosomal Abnormalities.” New York: Alan R. Liss for the National Foundation-March of Dimes, BD:OAS XIV(6C): 133-146.

Ponzio G, DeMarchi M, Gallone G, Fonzo D, Carbonara A 0 (1980): A Case of Klinefelter’s syndrome with 47,Xi(Xq)Y karyotype. J Med Genet 17:152-155.

Therman E, Sarto GE, Distieche C, Denniston C (1976): A possible active segment on the inactive human X chromosome. Chromosoma 59(2): 137-145.

Therman E, Sarto GE, Palmer CG, Kallio H, Denniston C (1979): Position of the human X inactivation center on Xq. Hum Genet 50(1):59-64.

Trunca C, Roginsky M, Ugrinsky C, Milson J (1979): 47,X,i(Xq)Y: An unusual chromosome comple- ment associated with the Klinefelter syndrome. Am J Hum Genet 31: 113A.

Zang KD, Singer H, Loeffler L, Souvatzoglou Halbfaas J, Mehnert H (1969): Klinefelter-syndrom mit dem Chromosomensatz 47,XXqiY. Klin Wochenschr 47:237-244.

Edited by James F. Reynolds