Uveal Coloboma and True Klinefelter Syndrome - Journal of Medical ...

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Journal of Medical Genetics (1970). 7, 213. 

Uveal Coloboma and True Klinefelter Syndrome 

J. FRAN(;OIS,"* M. Th. MATTON-VAN LEUVEN, and Ph. GOMBAULT 

The clinical features of 'Klinefelter' syndrome 

were first described by Klinefelter, Reifenstein, and 

Albright (1942). The true Klinefelter syndrome 

is chromatin-positive and is due to X chromosome 

polysomy, most frequently 47,XXY (Jacobs and 

Strong, 1959), but karyotypes with one or more 

X's or Y's additional to the XXY formula, such as 

48,XXXY, 49,XXXXY, and mosaicisms of XXY 

with other stem-lines, are variants of the syndrome 

(Barr et al., 1959; Ford et al., 1959; Fraccaro and 

Lindsten, 1960; Muldal and Ockey, 1960; Ellis 

et al., 1961; Harnden and Jacobs, 1961). The somatic 

abnormalities of the syndrome are relatively 

minor, especially at an early age and mostly only observed 

at or after puberty. They are: hypogonadism, 

testicular underdevelopment and atrophy 

(hyalinization of seminiferous tubules), inconstant 

gynaecomastia, and hormonal deviations, such as 

increased excretion of gonadotrophins. The following 

extragenital manifestations are frequent: poorly 

developed musculature, osteoporosis, skeletal anomalies, 

cutaneous angiomata, and mental retardation. 

The clinical picture of XXXY and other variants 

is similar to that of XXY subjects, though there 

seems to be a higher frequency of additional congenital 

abnormalities. 

The purpose of this paper is to report the presence 

of bilateral uveal coloboma in a 46,XX/47,XXY 

chromatin-positive boy. 

Case History 

This boy (H. Franky) was referred to us at the age of 4 

months; he was the son of healthy but consanguineous 

parents (Fig. 1), both aged 23 years, after a full-term 

uneventful pregnancy. The mother had had one x-ray 

of the abdominal region at the age of 15 years after an 

injury. The child had seizures on the 5th day, which 

lasted 20 minutes. The temperature and blood calcium 

levels were normal. 

Intramuscular administration of phenobarbitone 

(25 mg.) was helpful. Three days later, there was sudden 

high fever and his general condition became poor, due to 

* Address: Cytogenetics Laboratory, Ophthalmological Clinic of 

the University of Ghent, De Pintelaan 115, Ghent, Belgium. 

213 

a urinary infection (Esch. coli) which was treated with 

'pentrexyl'. The EEG was disturbed and showed 

paroxysmal bisynchronous spike waves. After a week 

the patient was free of fever and urography was normal. 

The EEG returned to normal. 

The patient's physical and psychological development 

continued satisfactorily and he could walk without 

help at 12 months. The genitalia were normally developed 

for his age: both testes had descended since 

birth (Fig. 2). 

Ocular examination. This revealed bilateral coloboma 

of the iris (Fig. 3) and choroid, more pronounced 

in the right eye, where it included the optic nerve. In 

the left eye, the macular region and optic nerve have 

been spared. Both fundi had an albinoid aspect, normal 

for his age. 

The child was last seen at the age of 16 months. He 

was alert and his mental status seemed entirely normal. 

Careful questioning of the parents and personal examination 

of several members of the proband's and of the 

parents' generation did not reveal the occurrence of a 

colobomatous lesion or equivalent. 

FIG. 1. Consanguinity of the proband's parents.



214 Frangois, Matton-Van Leuven, and Gombault 

Cytogenetic examination. This was performed in 

leucocytes, cultured following a micromethod seen in 

Professor Lejeune's laboratory. A total of 75 cells was 

analysed numerically. In 5 cells, 2 or more chromosomes 

had been lost during the techmcal in vitro 

manipulations. In the remaining 70 cells, 2n was distributed 

as follows: 45: 8%/', 46: 37%, 47: 490o, and 

48: 6%. In each of these groups, karyotypes were 

\ Ww analysed (28 in total). Of the cells with 2n=47, 

11 karyotypes were prepared. They constantly were 

47,XXY (Fig. 4). Of the cells with 2n=46, 12 karyotypes 

x a _ s:were analysed: 10 of them were 46,XX (Fig. 5) and 2 

of them were 46,XY. Of the cells with 2n = 45, 3 karyotypes 

were analysed: 2 of them had lost an autosome 

each in a different group and could be interpreted as 

45,XX; the remaining one had an autosome missing in 

.........;. f the C group and could be interpreted as 45,X. Of the 

FIG. 2. Outer genitalia. cells with 2n = 48, 2 karyotypes were prepared: one could 

be interpreted as 48,XXXY and the other possibly as 

48,XXYY. 

The sex chromosomal configuration is thus distributed 

in the 28 karyotypes as follows: XX in 12 karyotypes 

(43%O); XXY in 11 (39%); XY in 2 (7%); XXXY in 1 

.... (35%); XXYY in 1 (3,5%); XO in 1 (in vitro loss?) 

(3-5%). 

Structurally, the chromosomes were normal. In 

many karyotypes, however, the Y chromosome had long 

long arms. The mean Y/F index, i.e. the total length of 

the Y expressed as a ratio of the mean total length of the F 

chromosomes, was 0-96. The karyotypes were the result 

of three different blood cultures: the first time only 

XXY karyotypes were obtained. As the quality of the 

metaphases was not very good, a second blood culture 

revealed a high majority of cells with 46,XX. A third 

culture revealed a majority of cells with 47,XXY. 

The sex chromatin was evaluated in buccal mucosa on 

three occasions by the same observer: the first time Barr 

FIG. 3. Bilateral iris coloboma. bodies were seen in 12o% of the cells (orcein stain), the 

:. .. :: ... s ;: . . .s; - , : .:........ 

...... ...-RRSo "-'';...................... 

A.. > &.: ,:' 

............................................ b': 

.~~I...... ...... .... ... ... 

-: '.-;.. ....... '- -. .A 

* ...... .. .-eE y E - . ' ........ . f X -; . y; ;-X~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ....... .. .. .. ... 

119 ........... X i _ ... ...... 

.......... ... .. a._ ........ ...:t_:.- 

_._?... :........ ...:..... ...... 

. --::--. 

.. * W0JU, 

' ';'X' '........::. y'' 

1 ... . : .~~~~~~~~~....... 

:.: :; 

* Z : 

,,,.:.::;:. . 

4Ut:Q : 

FIG. 4. Karyotype with 2n = 47,XXY (propositus). 

;:::. ::............. 

'M




,,,., %....A 

second time in 160o (orcein stain), the third time in 10% 

(Shorr stain). These results indicated the presence of 

two X chromosomes. 

The drumstick evaluation revealed 0-4% polymorphs 

with a drumstick appendage. The lobulation of the 

polymorphs was extremely low. 

Cytogenetic evaluation was also performed in the 

patient's parents. The karyotype of the mother was 

normal (46,XX), both numerically and structurally. 

The karyotype of the father was numerically normal 

(46,XY). Structurally, most karyotypes showed a long 

Y chromosome, the relative length of which was generally 

even longer than in the proband (Fig. 6). The mean 

Y/F index was 1-13. 

Dermatoglyphic examination (Table I). This 

was carried out on the proband and his parents. 

Total finger ridge count. Proband, not determined; 

ulnar loops on all fingers, except on right thumb on 

which a whorl was present. Father, 68; mother, 146. 

Axial triradius and atd angle. Proband, distal displacement 

to position t", more pronounced on the left 

FIG. 6. G group chromosomes in karyotypes of the patient and his 

father. 

FIG. 5. Karyotype with 2n=46,XX (propositus). 

hand; atd right, 570; atd left, 68°. Father, triradius in 

position t; atd right, 430; atd left, 40°. Mother, distal 

displacement of axial triradius to position t'; atd right, 

48°; atd left, 540. 

Digital triradii. Proband, left hand; triradius c absent. 

Father, all present; mother, all present. 

a-b ridge count. Proband, right 32, left 40, summed 

72. Father, right, not counted because of burn scars; 

left 40. Mother, right 37, left 37, summed 74. 

............. 

TABLE I 

FORMULAE OF DERMATOGLYPHS 

Main Line Index 

Proband r fRight Left 11.9.0.5'.13.t'.0.0.0.0.0 11.9.7.5'.13.tr.O.O.O.L.0 16 

Father fRight Not RLeft 11.7.7.3.13.t.O.O.O.O.L determined 

14 

Mother fRight 9.9.57.5'.13t'°.O.O.O.L.D 14 

Left 11.9.7.5.'.13.t'.O.O.O.L.0 16 

215 

Discussion 

A: Sex Chromosomal Anomalies 

The sex chromatin values suggested the presence of 

two X chromosomes. The extremely low nuclear 

lobulation of the polymorphonuclear leucocytes, 

observed in our proband, has been reported as 

typical for Klinefelter syndrome (Mittwoch, 1964; 

Fr0land, 1969). 

The blood cultures revealed the presence of two 

main cell lines of about equal importance: 46,XX/ 

47,XXY. The XX/XXY type of mosaicism has 

been reported a few times in the Klinefelter 

syndrome (Ford et al., 1959; Hayward, 1960; 

Rohde, 1963; Court Brown et al., 1964).

216 



Three questions have to be answered: 

(1) Do these two cell lines exist in vivo ? 

(2) If they exist in vivo, how did they arise and 

how are they distributed in the patient ? 

(3) Have the minor cell lines 45,X, 46,XY, 

48,XXXY, and 48,XXYY originated in vitro 

through erroneous mitoses, or do they also exist in 

vivo ? 

Though the different ratios obtained in the three 

cultures might indicate the origin or the preferential 

growth of one of the cell lines in vitro, we feel that 

the two main cell lines exist in vivo and that the 

patient's karyotype is 46,XX/47,XXY. Indeed, 

our results were obtained from short-term blood 

cultures in which only one or two mitoses take 

place, and in which it is less likely than in long-term 

fibroblast cultures that selective forces for preferential 

growth for one or other cell line play an important 

role, or that a cell line with a karyotype other 

than the original one arises. 

There are two ways in which the two main cell 

lines may have arisen in the patient. 

(1) From an XY zygote. This hypothesis requires 

the occurrence of at least 2 successive mitotic 

errors: (a) mitotic nondisjunction of the X chromosome 

at the first division of the XY zygote, with 

production of XXY and YO cells and loss of the 

non-viable YO cell; (b) further early post-zygotic 

mitotic error, i.e. the loss of a Y chromosome at 

division of an XXY cell with production of XXY 

and XX cells. 

(2) From an XXY zygote. This requires the 

subsequent occurrence of two different pathological 

conditions: an imbalanced gamete and erroneous 

somatic mitoses at or shortly after the first cleavage 

division. 

(a) Imbalanced gamete. As the parents' karyotypes 

were normal, the possibility of a parental 

numerical chromosomal abnormality can be ruled 

out. The possibility of a gametogenetic error 

can neither be proved nor rejected. The hypothesis 

of meiotic nondisjunction could not be substantiated 

by data on the parents' ages which were 

normal (i.e. both 23 years), or by other cases of 

aneuploidy in the family, or by a history of a virus 

infection of the mother. The x-ray examination of 

the abdominal region at the age of 15 years can be 

rejected as responsible for an erroneous cell division 

taking place years later at ovulation. 

The father had, however, an unusually long Y 

chromosome. The question whether such a Y can 

determine abnormal behaviour of the XY bivalent 

at meiosis with consecutive nondisjunction is not 

Frangois, Matton-Van Leuven, and Gombault 

yet solved. More reports on the presence of long Y 

chromosomes in the families of aneuploid patients 

are needed to evaluate a possible causal relation. 

In order to have an idea of the variation of the 

length of the Y chromosome in the Belgian population, 

we determined the Y/F index in the karyotypes 

of 120 males who were referred to our laboratory, 

either as patients or as normal relatives of 

affected subjects. This control series had a Y/F 

index= 087 + 0-16. 

Data from published reports on the Y/F value are 

as follows: 088±0-11 in Asiatic Indians, 1-00+ 

0-15 in Japanese, 0-92 ± 0-09 in American Negroes, 

0 94 + 0 10 in Jews of eastern European extraction, 

and 0-86 ± 0 09 in non-Jews of Anglo Saxon origin 

(Cohen, Shaw, and MacCluer, 1966). In Japan, 

the Y/F was reported to vary between 0-78-0-93 in 

control patients with a normal Y, and between 

1-07-1-56 in patients with a long Y (Makino et al., 

1963; Tonomura and Ono, 1963; Makino and 

Takagi, 1965). 

Though it is mostly accepted that a long Y 

chromosome is a variation of the normal karyotype, 

its presence in association with somatic and genital 

malformations, and also in association with other 

karyotypic anomalies, might indicate a possible adverse 

effect. Association of a long Y chromosome 

with sexual anomalies was reported by Van Wijck, 

Tijdink, and Stolte (1962), de la Chapelle and 

Hortling (1963), Gropp et al. (1963), Gustavson et 

al. (1964b), Makino et al. (1964), Makino and Takagi 

(1965), Kjessler (1966), Fraccaro et al. (1966), 

Nusso et al. (1967), Beer, Pfeiffer, and Dammer 

(1 967), and Dumars and Fisher (1968). Association 

of a long Y chromosome with other cytogenetic 

abnormalities was observed in trisomy 21 (de la 

Chapelle and Hortling, 1963; Jacobs and Harnden, 

cited by Penrose, 1961; Bishop, Blank, and Hunter, 

1962; Gripenberg, 1964; Makino and Takagi, 

1965). Familial occurrence of a long Y chromosome 

in families with a mongoloid proband was 

noted by Bishop et al. (1962), Dekaban, Bender, and 

Economos (1963), and Makino et al. (1963). 

A mosaic karyotype similar to the one found in 

our patient, 46,XX/47,XXY, where the Y chromosome 

was long, was reported by Burgio, Severi, and 

Biscatti (1965) in a patient with a right endoabdominal 

testis and left gonadic agenesis. 

Comparison of the Y/F index of our proband 

(0 96) and of his father (1 -13) with, on the one hand 

the data from published reports, and on the other 

hand the values in the Belgian controls, shows that 

the father certainly has a longer Y chromosome than 

normal, but that the proband, though at the upper 

limit, is still within the normal variation. This is a



puzzling fact. However, in the karyotypes which 

showed 5 chromosomes in the G group, the 5th 

chromosome was interpreted as a Y. Indeed, if 

there were an autosomal anomaly, the child would 

be expected to be mentally retarded, which is not 

the case in our proband. The child is well developed 

both physiologically and psychologically 

and is by no means mentally retarded. 

(b) Mitotic error in the 47,XXY foetus, early 

post-zygotic after the first cleavage division, such as 

the following: 

(i) Somatic non-disjunction of 47,XXY cells with 

production of either 48,XXXY and 46,XY cells or 

46,XX and 48,XXYY cells. This is not very likely 

in view of the percentages obtained for the different 

cell lines. 

(ii) Direct loss of a Y chromosome giving rise to 

47,XXY and 46,XX cells, which is more likely to 

have occurred. 

The percentages suggest that whether the karyotype 

of the zygote was 46,XY or 47,XXY, a divisional 

error (including loss of a Y chromosome) 

must have occurred very early, resulting in the production 

of 46,XX and 47,XXY cell lines in about 

the same quantity. 

Mitotic errors may have occurred occasionally in 

the XXY cells, with production of the minor cell 

lines, 45,X, 46,XY, 48,XXXY, and 48,XXYY, 

either very late in embryonic life or in vitro during 

culture. In view of the extremely low frequency 

of these cell lines, it was impossible to judge 

whether they represented true mosaicism or accidental 

deviations. The 46,XY configuration was 

indeed found only in two and the 48,XXXY, 

48,XXYY, and 45,X configurations, respectively, 

only in one karyotype, whereas the 47,XXY and 

46,XX cells represented the great majority of cells. 

It was impossible to perform a skin or fascia 

biopsy so that the frequency of the different cell 

lines in tissue other than blood could not be studied. 

In any case, blood mosaicism indicates that the 

error must have occurred at or before the gastrula 

stage, i.e. around or shortly after the 14th day. 

The clinical picture of mosaic patients is probably 

less dependent on the number of cell lines 

than on the relative frequency of the cells in each 

cell line. This frequency depends on the stage of 

embryonic development at which the non-disjunction 

which causes the mosaicism takes place. The 

earlier mosaicism originates in embryonic life, the 

more severe probably is the influence on the phenotype. 

The relative influence of the different cell 

lines will only become evident at puberty. Repeated 

cultures are sometimes necessary in order to 

reveal the existence of mosaicism. A mosaic 


217 

pattern can indeed be overlooked if an inadequate 

number of cells is counted. We can compare in 

this respect our patient with the patient reported by 

Hecht et al. (1966) who was originally described as a 

46,XX patient without Y chromosomes, in whom, 

when further investigations were carried out, a 

mosaic cell line (1 %) was detected. 

B: Coloboma 

Coloboma results from abnormal closure of the 

foetal cup cleft soon after gastrulation at the end of 

the first or the beginning of the second foetal 

month, when the optic vesicle is in an active state of 

differentiation (Duke-Elder, 1940; Mann, 1957). 

This faulty development of the ectodermal eye 

structures can be caused by chromosomal, Mendelian, 

and environmental intrauterine teratogenous 

factors. 

(I) Chromosomal anomalies. Coloboma and 

other eye defects have been found in anomalies of 

all the autosomal groups and are not specific for any 

particular chromosomal abnormality: A group 

(Lele, Dent, and Delhanty, 1965; El Massri and 

Riad, 1965), B group (Hirschhorn and Cooper, 

1961; Hirschhorn, Cooper, and Firschein, 1965; 

Gustavson et al., 1964b; Shaw, Cohen, and 

Hildebrandt, 1965; Wolf et al., 1965; D. Jesberg, 

personal communication, 1966), C group (Salonius 

and Opitz, 1964), D group (Patau et al., 1960), 

and E group (Francois et al., 1965; D. Jesberg, 

personal communication, 1966). 

Colobomatous lesions of the eye ball have not 

been found in trisomy 21. 

A t(B/G) translocation trisomy was found in a 

child with multiple anomalies among which were 

blepharophimosis and colobomata of the irides 

(Gustavson et al., 1964a). Uveal colobomata are 

part of the oculo-anal syndrome, which is caused by 

an extra small submedian chromosome in girls 

with mongoloid slant of the eyelids, hypertelorism, 

microphthalmia, anal atresia, recto-vaginal fistulae, 

pre-auricular fistulae, renal malformations, and 

mental retardation (Schachenmann et al., 1965; 

Cagianut, 1968). 

Colobomata were also found associated with 

oligophrenia, various congenital abnormalities, 

exotropia, myopia, and the presence of a small 

extrametacentric chromosome in a sex chromatinnegative 

boy (Heimann, Jaeger, and Dollmann, 

1968). 

The importance of a chromosome aberration as a 

causal factor should not be overstressed. 

(i) In the case of autosomal aberrations, the coloboma 

is only part of the general pathological 

condition.

218 



(ii) Chromosomal aberrations are usually absent 

in cases of isolated coloboma with an otherwise 

normal phenotype. 

(iii) When a coloboma is found in association with 

a chromosomal peculiarity, but when the latter is 

also present in one of the phenotypically normal 

parents (Lele et al., 1965), the causal relation between 

the coloboma and the chromosomal peculiarity 

becomes doubtful. 

(iv) There exist several reports of coloboma 

patients with associated multiple congenital malformations, 

who had a normal karyotype (Edwards, 

Young, and Finley, 1961; Angelman, 1961). 

In sex chromosomal aberrations, ocular anomalies 

are infrequent and uveal coloboma is exceptional. 

In the Klinefelter syndrome the eyes are usually 

normal. Other severe somatic malformations are 

also extremely infrequent. A possible explanation 

is that the major part of the extra X chromosome is 

genetically inactivated. Out of the impressive 

bibliography on Klinefelter syndrome, including 

review studies on large series (Court Brown et al., 

1964; Froland, 1969), on smaller series, and the 

numerous individual case reports (Nowakowski, 

1961; de la Chapelle and Hortling, 1963; 

Prader, Murset, and Hauschteck, 1964, etc.), totalling 

400-500 karyotyped or sex chromatin typed 

Klinefelter patients, the following ocular morphological 

features were noted. 

47,XXY karyotype: Myopic astigmatism (Nowakowski, 

1961, case 6), high myopia (Nowakowski, 1961, case 7), 

bilateral coloboma of iris and choroid (Appelmans, 

Michiels, and Guzik, 1965), Marfan syndrome (Bessiere 

et al., 1962), pigmentary retinopathy (Nagy, Leowei, and 

Kakuk, 1965), associated achondroplasia, and posterior 

corneal dysgenesis and atrophy of iris root, condensations 

of the Schwalbe ring, and abnormal insertion of iris root, 

forming radial arcades which masked the ciliary band 

(Amalric et al., 1966), hypertelorism in a premature child 

with multiple malformations and triploidy (2n = 69: 

66A + XXY) (Bernard et al., 1967). 

48,XXXY karyotype. Severe myopia (Ferguson- 

Smith, Johnston, and Handmaker, 1960). 

49, XXXXY karyotype. Esotropia and myopia (-18D) 

(Anders et al., 1960), hypertelorism (Fraccaro, Klinger, 

and Schutt, 1962; Barr et al., 1962), hypertelorism, 

epicanthus, strabismus internus concomitans, myopia 

(- 3D) (Pfeiffer, 1962), alternating esotropia and hypertropia 

caused by obvious overaction of the inferior 

obliques (Atkins and Connelly, 1963), conspicuous 

epicanthus (Farquhar and Walker, 1964), hypertelorism, 

palpebral fissures, slanting downwards and medially 

(Joseph, Anders, and Taylor, 1964), strabismus (Fraser 

et al., 1961), divergent strabismus and hypertelorism 

(Barr et al., 1962), strabismus, bilateral coloboma of 

iris and optic nerve (Joannides and Tsenki, 1968), 

pronounced epicanthus (Froland, 1969, case 47), 


pronounced epicanthus, slight hypertelorism, alternating 

external strabismus, high myopia (-20D), and myopic 

fundus degeneration (Froland, 1969, case 48). 

49,XXXYY karyotype. Blepharophimosis and prominent 

supra-orbital ridges (Bray and Ann Josephine, 

1963). 

48,XXYY karyotype. Cataract, strabismus, high myopia, 

and choroidal atrophy (Laurence, Ishmael, and 

Davies, 1963), epicanthus (Mirouze et al., 1964), 

myopia (Herbeuval et al., 1965), iris aplasia (Warburg, 

1968), prominent supra-orbital ridges (Ellis et al., 

1961). In a case of Amalric et al. (1966) there was a 

uveal dystrophy: iris atrophy and atrophic insertion of 

this iris root. The iris atrophy was more pronounced in 

the periphery. The sphincter zone was yellow. The 

zone of the dilator muscle fibres was grey. This bicolour 

iris atrophy reminded one of the atrophies found 

in genetic mesodermal syndromes. Atrophy in the 

chamber angle was especially pronounced between 4 and 

6 o'clock. The iris root continued there only in a thin 

grey-yellow strip, attaching itself very high up. This 

atrophic iris insertion masked all the underlying structures. 

Mosaic karyotypes 

48,XXYY/49,XXXYY: epicanthus, right iris coloboma, 

and bilateral choroidal colobomata adjacent to the 

papilla in a 48, XXYY/71, XXXYY infant with peculiar 

facies, syndactyly, and multiple minor malformations 

(Schmid and Vischer, 1967). 

47,XXY/46,XX/46,XY/45,X: severe myopia and pigmentary 

retinopathy (Nowakowski, 1961; Bergman, 

Nowakowski, and Reitalu, 1969). 

47,XYY/48,XXYY: Prominent supra-orbital ridges 

and myopia (Spencer, Eyles, and Mason, 1969), prominent 

supra-orbital ridges and optic atrophy (Spencer 

et al., 1969). 

48,XXXY/49,XXXXY/50,XXXXXY: high myopia 

(- 18D) and convergent strabism (Anders et al., 1960). 

Long Y: coloboma, developmental errors of the brain 

and the heart, cleft scrotum, small penis, in a child in 

whom 'preliminary investigations pointed to some 

chromosome abnormality' (Angelman, 1961): the boy 

had 46 chromosomes, but had a larger Y than normal 

(H. Angleman, personal communication, 1969). 

47,XXY+ chromosome resembling a no. 15: myopic 

astigmatism (Nowakowski, 1961: Case 9), myopia 

(Nowakowski, 1961: Case 11). 

This review shows that the association of coloboma 

with Klinefelter syndrome has been reported 

only three times (Appelmans et al., 1965; Schmid 

and Vischer, 1967; Joannides and Tsenki, 1968). 

To our knowledge, our proband is the fourth case. 

In this connexion it is interesting to note that the 

peculiar iris observed by Amalric et al. (1966) in the 

48,XXYY Klinefelter patient and in the 47,XXY 

Klinefelter/achondroplasic patient, was most pronounced 

at the lower half of the angle, i.e. at the 

localization of the foetal cleft. The lesions found



in the anterior chamber were classified by these 

authors as belonging to the malformative group of 

cleavage of the anterior chamber together with other 

pathological conditions, such as persistence of 

mesenchymatous tissue, posterior embryotoxon, 

hyaline corneal membrane, posterior marginal dysplasia 

of Streiff, and mesodermic dysgenesis of 

Rieger (Amalric et al., 1966). 

The small number of reported ocular anomalies 

in the Klinefelter syndrome might be due to incomplete 

examination of the patient, omitting an 

ophthalmological examination, or to the fact that 

the ocular functions are not always disturbed, so 

that the patient does not complain and is not referred 

to an ophthalmological department. The 

frequent associated mental retardation also makes 

complete ophthalmic examination difficult. Coloboma 

of the iris, being an easily seen congenital 

anomaly, is however not likely to be overlooked, or to 

be omitted in a report when it is present in a patient. 

We examined extensively the eyes of 3 adult 

Klinefelter patients, including evaluation of the 

refraction, mobility, fundus, and anterior chamber 

angle: these patients were karyotyped in our 

laboratory and all were 47,XXY, and we did not 

notice any ocular abnormality (Table II). 

The results of different sex chromatin surveys in 

newborn males, normal adult males, males with 

mental retardation, and other institutionalized 

patients, indicated that an additional X chromosome 

was present in some or all of the cells of 2-07 per 

1000 newborn male babies and of 1 96-2-18 per 

1000 adult males (Prader et al., 1958; Moore, 1959; 

Berlemann, 1961; Maclean, Harnden, and Court 

Brown, 1961; Maclean et al., 1964; Paulsen et al., 

1964; Maclean, 1966; Taylor and Moores, 1967; 

Maclean et al., 1968; Fr0land, 1969). 

Coloboma of the iris is judged to have an incidence 

of about 1:6000 (Duke-Elder, 1940), i.e. 

1:12,000 males. Knowing that the frequency of 

Klinefelter syndrome is 2:1000 males, it can be 

calculated that there is a probability of about 1 in 6 

million that the two conditions would occur in the 

same individual by chance alone. 

The fact that in the published reports of 400-500 

karyotyped or sex chromatin-typed Klinefelter 

patients, coloboma was found 4 times ( ± 1%), can 

indicate that coloboma may possibly be part of the 

phenotypic expression of Klinefelter syndrome, 

though the causal mechanism remains entirely obscure. 

The idea has gained ground that the human sex 

chromosomes act in two different ways (Commoner, 

1964). 

(a) The euchromatic X chromosome exerts its 


219 

influence via sex-linked Mendelian genes and control 

biochemical specificity. (b) The second heterochromatic 

X chromosome would act as an agent of 

nucleotide sequestration and regulate metabolic 

processes, which result in quantitative differences. 

The difference between the sexes would be of a 

quantitative rather than of a qualitative nature, and 

would not be correlated with any biochemical 

specificity. In this respect, Klinefelter patients can 

be considered as males having a quantitatively altered 

production of sex hormones. According to Ohno 

(1967) and Mittwoch (1967), the metabolic pathway 

of steroid sex hormone synthesis is such that 'the 

functional difference between androgen-producing 

interstitial cells and estrogen-producing follicular cells 

is not qualitative, but quantitative. The former inhibits 

further conversion of androstenedione, while 

the latter does not permit the accumulation of androstenedione, 

but converts it further to estrone.' 

(II) Mendelian heredity. Though uveal coloboma 

occurs most frequently as a sporadic condition, 

it can be familial and is then usually transmitted as 

an irregular dominant trait. On rare occasions, 

however, recessive transmission has been reported 

(Waardenburg, 1934; Gesell and Blake, 1936; 

McLain and Dekaban, 1963). Consanguinity of 

the parents was reported by Waardenburg (1932). 

We have observed an occurrence of coloboma of 

the uvea, which can best be explained by recessive 

transmission rather than by dominant transmission 

(Franqois, 1966): a father and a daughter are 

affected, but the mother also has a nephew who 

suffers from it. Therefore, a marriage between a 

homozygote and a heterozygote giving rise to the 

manifestation in the daughter (pseudo-dominance) 

could be postulated. 

Isolated cases of Klinefelter syndrome have been 

associated with other Mendelian diseases, such as 

Ehlers-Danlos syndrome (Hsu, Geller, and Nemhauser, 

1966), achondroplasia (Sendrail et al., 

1967),* familial spino-cerebellar degeneration,t 

(Indemini and Ammann, 1961), and thyroid hypofunction 

(Herbeuval et al., 1968). In the present 

case family data were entirely negative. So, though 

the parents were consanguineous, the chance exists 

that the coloboma in our proband is not due to 

Mendelian heredity. 

(Ill) Disturbed embryogenesis. As possible 

adverse influences on the closing of the optic cup the 

following have been suggested: inflammation 

* The frequency of achondroplasia is estimated to be around 0.1 

per 1000; it is inherited either in a dominant or a recessive mode. 

t In a sibship of 5, Klinefelter syndrome was associated with a 

neurological syndrome including ocular manifestations; 3 sibs had a 

paresis of an external ocular muscle; 2 had Fuch's heterochromia.

220 



(Mann, 1957), vascular defect (Stroeva, 1961), 

germinal defect in the epiblast (Von Szily, 1924), 

and defect in the mesoblastic tissue surrounding the 

optic cup (Von Hippel, 1903). 

C: Dermatoglyphs 

Developmental disturbances taking place during 

the third and fourth months of foetal life affect the 

arrangements of the dermal ridges. Contrary to the 

specific dermatoglyphs, discernible on first view, 

which are found in autosomal trisomies, the peculiarities 

in Klinefelter syndrome are mainly quantitative, 

and consist of a tendency to fingertip patterns 

with a low ridge count. Many loops have so few 

ridges that they constitute a transition to arches. 

The frequency of true arches is also increased. The 

mean total finger ridge count (TFRC) of Klinefelters 

(1178) was found to be about 30 ridges 

lower than the mean of control males, and about 

9 ridges lower than the mean of control females. 

As in all races, normal females have more arches, 

fewer whorls, and lower ridge counts; this finding 

has been interpreted as suggestive for sex reversal 

(Forbes, 1964). 

Our proband could not be tested for fingertip 

counting. His father had a very low TFRC (68), 

whereas his mother had a high TFRC (146). 

The axial triradius tends to be situated low in the 

palm in Klinefelter patients (Holt, 1968), corresponding 

with a normal maximum atd angle. Surprisingly, 

our proband's axial triradius is displaced 

distally, a phenomenon that is not typical of 

Klinefelter syndrome. 

According to Holt (1968), genetic as well as environmental 

factors must play a role in the determination 

of the position of the axial triradius. In 

this respect it must be mentioned that the atd 

angles of the father were normal, i.e. less than 450 

(corresponding with position t of the axial triradius), 

but that the atd angles of the mother were intermediate 

(490 and 540) corresponding with position 

t' of the axial triradius. This makes it difficult to 

judge whether the distal displacement of the axial 

triradius in the proband is inherited from the mother 

or whether it reveals an intrauterine disturbance 

during the third or fourth month. 

The fact that the triradius c was absent needs to 

be stressed. An absent triradius c on both palms, 

d being sited nearer to the radial border of each 

palm than normal, was reported by Jancar (1964) 

in a 49,XXXXY patient. Vague et al. (1968) reported 

Klinefelter syndrome in monozygotic twins, 

in one of whom triradius c was absent on the left 

hand. In our own series, the triradius c was absent 

in the proband and in another patient on the left 


TABLE II 

OCULAR AND DERMATOGLYPHIC 

EVALUATION OF KLINEFELTER PATIENTS 

Patient Karyotype Dermatoglyphs Eye 

V. d. V. Willy 47,XXY 

TFRC low (42); 

bilateral, very 

proximal 

Normal 

V. E. Gerard 47,XXY Normal Normal 

V. C. Eric 47,XXY 

Left hand, 

absent 

triradius c 

Slight 

astigmatism, 

otherwise 

normal 

H. Franky 46,XX/47,XXY 

Bilateral distal 

displacementBiael 

to tr of axialBiael 

triradius; left coloboma of 

hand, irss and 

triradtius c choroid 

absent 

hand (Table II, V. C. Eric). It has to be remembered, 

however, that even in a normal population in 

some palms one of the digital triradii, most commonly 

c, is absent. More data on dermatoglyphs 

in Klinefelter patients are needed in order to interpret 

this finding. 

In Klinefelter syndrome the distance between 

triradii a and b tends to be shortened as compared 

with the distance in the general population, where 

the range of ab counts summed for both hands lies 

between 47 and 122 ridges. The ab ridge count is 

genetically controlled, though environmental factors 

exert a greater effect on the ab ridge count in early 

prenatal life than they do on the finger ridge count 

(Holt, 1968). The ab ridge count of our family 

did not allow any conclusion regarding a possible 

diminution of the a-b distance in the proband. 

As can be seen from the palmar formulae, the 

direction of the main lines is normal, and no special 

patterns were present in the thenar or hypothenar 

areas. The main line indices were also within 

normal range, as compared with the mean main 

line index of the population: 16 38 (Holt, 1968). 

Conclusions 

The proband presents the association of three 

pathological conditions which may have arisen at 

different embryonic stages. 

(1) Sex chromosomal aneuploidy and mosaicism 

47,XXY/46,XX around or shortly after the 14th day. 

(2) Uveal colobomata at the end of the first or the 

beginning of the second foetal month. 

(3) Abnormal dermatoglyphs during the third or 

fourth months. 

Whether the three conditions are causally linked 

can neither be proved nor rejected. Published data 

indicate however that coloboma may be part of the



phenotypic expression of the Klinefelter syndrome. 

Except for the consanguinity of the parents, no 

familial data indicate a possible Mendelian origin of 

the coloboma, so that it can also be the result of disturbed 

embryogenesis. 

The major cell lines, 46,XX and 47,XXY, are 

assumed to be present in the proband and not to 

have arisen in vitro. The minor cell lines, 

48,XXXY and 48,XXYY, could be present in 

the patient, but might well have arisen in vitro. 

The mosaicism can as well have arisen from an XY 

zygote as from an XXY zygote. In the latter 

case the father's long Y chromosome may have 

played a causal role in nondisjunction. In both 

cases a divisional error including the loss of a Y 

chromosome must have occurred early in the postzygotic 

stage. 

The effect of the mosaicism on the clinical (sexual) 

phenotype of the patient will only become evident at 

puberty. The abnormal dermatoglyphs are not 

typical for Klinefelter syndrome, and can be the 

result of a disturbed embryogenesis. The displaced 

axial triradius may however also be inherited 

from the mother. 

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Notes 

Uveal coloboma and true 

Klinefelter syndrome. 

J François, M T Leuven and P Gombault 

J Med Genet 1970 7: 213-223 

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