mixed gonadal dysgenesis: clinical, cytogenetic, endocrinological, and histopathological findings in...

American Journal of Medical Genetics 46:263-267 (1993)

Mixed Gonadal Dysgenesis: Clinical, Cytogenetic, Endocrinological, and Histopathological Findings in 16 Patients

Juan Pablo Mendez, Alfred0 Ulloa-Aguirre, Susana Kofman-Alfaro, Osvaldo Mutchinick, Carlos Fernhdez-del-Castillo, Edgardo Reyes, and Gregorio Perez-Palacios Departments of Reproductive Biology (J.P.M., A.U-A., G.P.P.), Genetics (OM.) , Gynecology (C.F-d-C.) and Pathology (E.R.), Instituto Nacwnal de la Nutricwn Salvador Zubiran; and Department of Genetics (S.K-A.), Hospital General de Mtkico, Mexico D.F.

We describe clinical, cytogenetic, endocrine, and histopathological findings in 16 patients with mixed gonadal dysgenesis (MGD). All patients except l presented genital ambiguity and 10 of them had Ullrich-Turner manifesta- tions. The 45,X/46,XY karyotype was the most frequent with a predominance of 45,X cells in both peripheral lymphocytes and gonads. In all cases Mullerian and Wolffian remnants and/or derivatives were found and in some patients both Wolffian- and Mullerian-de- rived structures were identified on the streak or testicular side. Postpubertal patients exhibited variable degrees of virilization and all of them had hypergonadotropism coexisting with low to normal baseline serum levels of testosterone; their testicular response to human chorionic gonadotropin (HCG) in terms of testosterone secretion was also variable, ranging from minimal to almost a normal response. All prepubertal patients but 1 had normal baseline levels of pituitary gonadotropins and testosterone and their gonadal response to the HCG challenge was highly variable. With the exception of 1 case, who had a 45X/46XY(p - ) karyotype, no correla- tion between the cytogenetic data and degree of external genital ambiguity and the hormonal findings was observed. Additional in- formation on the specific structural abnormalities involving the testis-determining gene of the Y chromosome in patients with MGD is needed in order to further understand the

Received for publication June 29,1992; revision received Novem- ber 23, 1992.

Address reprint requests to Juan P. MBndez, Department of Reproductive Biology, Instituto Nacional de la Nutrici6n SZ, Vasco de Quiroga 15, Tlalpan 14000, Mexico D.F., Mexico.

mechanisms responsible for the wide vari- ability characteristic of this disorder. 0 1993 Wiley-Liss, Inc.

KEY WORDS: postpubertal patients, karyotype, testosterone

INTRODUCTION Mixed gonadal dysgenesis (MGD) encompasses an

heterogenous group of different chromosomal, gonadal, and phenotypic abnormalities characterized by the presence of a testis on one side and a streak or an absent gonad at the other [Davidoff and Federman, 19731, per- sistence of Mullerian duct structures, and a variable degree of genital ambiguity. Ullrich-Turner syndrome stigmata and renal abnormalities may also be found; and some gonadal tumors, such as gonadoblastoma and dysgerminoma are frequently seen in patients with this disorder [Robboy et al., 1982; Rutgers and Scully, 1987; Wallace and Levin, 19901. Even though the characteristics of MGD have been extensively described in these studies, in most of them the endocrine findings are unre- ported and comments on the endocrine status of the patients, if included, are fragmentary. Here we analyze the main characteristics found in 16 patients with MGD and attempt to correlate their endocrine profile with the clinical, cytogenetic, and histopathological findings.

SUBJECTS AND METHODS The charts of 16 patients with MGD who were evalu-

ated and treated by the authors between 1980 and 1991 and in which surgical pathology material documented the presence of a testis and a contralateral streak were included in the analysis. None of them had received hormonal preparations as treatment of their condition. The first two cases (Table I) were reported in a previous study of patients with 45,X/46,XY karyotypes [Kofman- Alfaro et al., 19811. All patients had a complete clinical, cytogenetic, and endocrine evaluation which included measurement of the baseline levels of immunoreactive

0 1993 Wiley-Liss, Inc.

TAB

LE I

. C

linic

al, C

ytog

enet

ic, H

isto

path

olog

ical

and

Hor

mon

al F

indi

ngs

in 1

6 Pa

tient

s W

ith M

ixed

Gon

adal

Dys

gene

sis

Age

C

ase

(yr/

mo)

K

aryo

type

a

20/0

6/0

1 /4

2 /9

19/0

7/0

16/0

1 /4

45,X

/46,

XY

45,X

/46,

XY

45,X

/46,

XY

45,X

/46,

XY

45,X

/46,

XY

45,X

/46,

XY

45,X

/46,

XY

p -

45,X

/47,

XY

Y

Ullr

ich-

Tur

ner

stiw

ata

Shor

t le

ft 4

th m

etac

arpu

s an

d m

etat

arsu

s

Low

hai

rlin

e, s

hort

and

w

ebbe

d ne

ck, m

ultip

le

nevi

Fa

cial

asy

mm

etry

, hi

gh

pala

te,

low

hai

rlin

e,

shor

t nec

k Fa

cial

asy

mm

etry

, hi

gh

pala

te

Hig

h pa

late

, low

hai

rlin

e,

mul

tiple

nev

i

Gon

ads

and

inte

rnal

ge

nita

liab

(rig

ht s

ide/

LH

(m

IU/

Ext

erna

l ge

nita

lia

left

sid

e)

ml)

d

Phal

lus

8 cm

, per

inea

l hy

posp

adia

s, n

orm

al

pubi

c ha

ir

Phal

lus

3 cm

, pha

llic

hypo

spad

ias

Phal

lus

2.5

cm,

peri

neos

crot

al

hypo

padi

as

Phal

lus

2 cm

, pen

oscr

otal

hy

posp

adia

s

Phal

lus

10 c

m, p

erin

eal

hypo

spad

ias,

nor

mal

pu

bic

hair

Ph

allu

s 3

cm,

peri

neos

crot

al

hypo

spad

ias

Phal

lus

0.5

cm, f

emal

e

Phal

lus

2.5

cm, p

halli

c hy

posp

adia

s

Ingu

inal

tes

tis,

ep

idid

ymis

, vas

de

fere

ns/S

trea

k,

Fallo

pian

tube

St

reak

, Fal

lopi

an t

ube/

C

rypt

orch

idic

tes

tis,

ep

idid

ymis

, vas

de

fere

ns

Intr

ascr

otal

tes

tis,

ep

idid

ymis

"/St

reak

, Fa

llopi

an t

ube,

ep

idid

ymis

St

reak

, Fal

lopi

an t

ube,

ep

idid

ymis

iInt

rasc

rota

1 te

stis

, epi

didy

mis

' In

tras

crot

al t

esti

s,

epid

idym

is'/S

trea

k,

Fallo

pian

tub

e St

reak

, Fal

lopi

an t

ube,

ep

idid

ymis

hgui

nal

test

is, e

pidi

dym

is

Cry

ptor

chid

ic t

esti

s,

Fallo

pian

tub

e,

epid

idym

is/S

trea

k,

Fallo

pian

tub

e In

tras

crot

al t

esti

s,

epid

idym

is?S

trea

k.

38.0

1.5

1.2

0.8

14.5

1.8

43.0

1.6

FSH

(m

IU/m

l)d

42.0

0.6

0.7

1.0

23.5

0.9

51.5

0.5

Bas

al T

T

post

- (n

g/m

lld

HC

G~

3.

4

0.2

0.3

0.6

4.8

0.2

0.5

0.4

6.2

1.2

2.6

1.3

8.8

1.1

0.9

3.5

__ -

Fa

llopi

an tu

be

9 10

11

12

13

14

15

16

0/11

46

,XY

-

0111

45

,X/4

6,X

Y,id

ic(Y

) -

2010

46

,XY

H

igh

pala

te,

mul

tiple

ne

vi

118

45,X

/46,

XY

B

ilate

ral

shor

t m

etac

arpu

s “c

afe

au

lait”

spo

ts

011

45,X

/46,

XY

Sh

ort a

nd w

ebbe

d ne

ck

216

45,X

/46,

XY

,dic

(Y) -

2710

45

,X/4

6,X

Y,d

ic(Y

) Lo

w h

airl

ine,

sho

rt n

eck,

m

ultip

le n

evi

1/10

45

,X/4

6,X

Y

Low

hai

rlin

e, s

hort

and

w

ebbe

d ne

ck

Phal

lus

4 cm

, pen

oscr

otal

hy

posp

adia

s

Phal

lus

1 cm

, pe

rine

oscr

otal

hy

posp

adia

s Ph

allu

s 4

cm,

peri

neos

crot

al

hypo

spad

ias,

sca

nty

pubi

c ha

ir

Phal

lus

3 cm

, pen

oscr

otal

hy

posp

adia

s

Phal

lus

2.5

cm,

peno

scro

tal

hypo

spad

ias

Phal

lus

2.5

cm,

peno

scro

tal

hypo

spad

ias

Phal

lus

4 cm

, pe

rine

oscr

otal

hy

posp

adia

s, s

cant

y pu

bic

hair

Ph

allu

s 3

cm, p

enos

crot

al

hypo

spad

ias

Stre

ak, F

allo

pian

tube

1 C

rypt

orch

idic

tes

tis,

epid

idym

is

Stre

ak, F

allo

pian

tube

1 In

tras

crot

al t

estis

, ep

idid

ymis

‘ In

guin

al t

estis

, ep

idid

ymis

, vas

defe

rend

stre

ak,

Fallo

pian

tub

e,

epid

idym

is

Stre

ak, F

allo

pian

tub

e/

Intr

ascr

otal

tes

tis,

epid

idym

is‘

Stre

ak, F

allo

pian

tub

e,

epid

idym

islh

guin

al

test

is, e

pidi

dym

is

Stre

ak, F

allo

pian

tube

1 C

rypt

orch

idic

test

is,

Fallo

pian

tub

e,

epid

idym

is

Stre

ak, F

allo

pian

tub

e1

Intr

ascr

otal

tes

tis,

epid

idym

is‘

Ingu

inal

tes

tis,

epid

idym

idst

reak

, Fa

lloD

ian

tube

0.8

0.7

1.4

0.8

32.5

33

.7

4.6

0.5

10.3

2.

1

0.3

1.3

25.1

20

.5

1.6

0.7

0.1

0.6

1.9

1.6

2.2

0.1

1.2

0.9

2.2

2.9

2.3

4.7

4.7

0.9

2.4

3.0

.In p

erip

hera

l ly

mph

ocyt

es.

bAll

pati

ents

pre

sent

ed e

ithe

r in

fant

ile

or r

udim

enta

ry u

teru

s.

‘In a

ll in

tras

crot

al te

stis

onl

y te

stic

ular

bio

psy

was

take

n.

dRef

eren

ce va

lues

: Pos

tpub

erta

l men

, LH

: 3-1

2 m

IU/m

l; FS

H: 1

-5 m

IUlm

l; T:

3.5

-8.0

ngl

ml;

max

imal

T a

fter

HC

G: 9

to 1

6 ng

/ml.

Chi

ldre

n, L

H: 0

.5-5

.0

mIU

/ml;

FSH

: 0.5

-2.5

mIU

1ml;

T: 0

.07-

0.8

ng/m

l; m

axim

al T

aft

er H

CG

: 1.

5-4.

5 ng

/ml.

266 Mendez et al.

serum gonadotropins, 17P-estradiol (E2) and testosterone (T) as well as gonadal responsiveness to exogenous human chorionic gonadotropin (HCG) [Ulloa- Aguirre et al., 1988a,b]. In 13 cases chromosome analysis was per- formed on both peripheral lymphocytes and cultured biopsies from each gonad, streak and testis, whereas in the remaining 3 cases only on lymphocytes. The exact type of each gonad was determined by the criteria estab- lished by Robboy et al. 119821.

RESULTS AND DISCUSSION Individual clinical traits of the 16 patients analyzed

are shown in Table I. In 10 cases (cases 1, 2, 4-7, 12, 14-16), height was <3rd centile for normal Mexican individuals. Also, 10 of them (8 with short stature) exhibited Ullrich-Turner stigmata. Only 3 patients had renal anomalies (cases 5 and 7, horseshoe kidney and case 13, left ureteral stenosis) and in one case (case 15) aortic coarctation was observed. In all cases, except in patient 7, genital ambiguity was found and external genitalia tended to be more masculine than feminine, appearing as a bifid scrotum or rugated labioscrotal folds. All these patients had hypospadias of variable degree (Table I).

Chromosome analysis showed that all patients had a Y chromosome, including 13 with a 45,X/46,XY mosaicism (4 of them with structural abnormalities of the Y chromosome), 1 with a 45,X/47,XYY mosaicism, and 2 with an apparently normal 46,XY karyotype in lymphocytes (Table I). In cases 1,3,6,7, and 10 the proportion of 45,X and 46,XY cells observed in blood and gonads was similar (45,X cells in blood 74-92, in gonads 75-91; 46,XY cells in blood 6-26, in gonads 6-25), whereas in cases 2 ,4 ,5 ,8 , 12, 14, and 15 the 45,X cells exhibited a higher frequency in the gonadal tissue (54-100%) than in blood (10-48%), reaching 100% in cases 2 and 15. In case 12 a complex mosaicism (45,X/46,XY/47,XY +mar) was restricted to the gonads, and in case 9,100% of XY cells were found in both the gonads and blood.

All patients had persistent Mullerian structures which ranged from a normal to an infantile or rudimen- tary uterus. A Fallopian tube always accompanied the streak gonad. Interestingly, in 2 of the 4 patients with cryptorchidism (cases 7 and 14), a Fallopian tube was also found adjacent to the testis; all 4 of these cases had a well-formed ipsilateral epididymis. In 5 of the 16 patients, the opposite streak gonad also was associated with an epididymis. Gonadal tumors were found in 3 patients (cases 1 and 7, unilateral gonadoblastoma; and case 11, a left gonadoblastoma and a right seminoma with areas of embryonal carcinoma).

In all postpubertal patients (cases 1, 5,7, 11, and 15) serum levels of FSH and LH were significantly increased (Table I) with the exception of case 5, who showed serum LH concentrations marginally elevated (14.5 mIU/ml). In this latter patient, serum T was within the normal range, whereas in the remaining postpubertals the concentration of this androgen was decreased. Administration of HCG induced significant serum T increments in subjects 1 ,5 , and 15 and margi- nal rises in subjects 7 and 11. The lowest baseline and HCG stimulated serum T concentrations were exhibited

by patient 7, who had a female phenotype, a low percent- age of XY cells in both blood (8%) and gonads (9%), and structural abnormalities on the short arm of the Y chromosome (p-). Nine out of 11 prepubertal patients exhibited normal baseline levels of serum LH, FSH, and T. In case 13 (1 month old), serum LH and T concentrations were elevated; this finding agrees with previous reports showing that neonates may normally exhibit increased values of these hormones [Winter et al., 19761. The remaining case (case 12) presented serum LH levels in the upper limit of normality and increased baseline T concentrations. As it has been reported in normal children [Ulloa-Aguirre et al., 19851, prepubertal patients with MGD exhibited heterogeneous T responses to HCG administration which ranged from net T increments of 0.7-0.8 ng/ml (cases 4 and 14) to increments up to 3.1 ng/ml (cases 8 and 12). In all prepubertal and postpubertal cases serum E, was <15 pgtml. With the exception of case 7, we did not find any clear relationship between the hormonal profile and the clinical (e.g., degree of genital ambiguity), cytogenetic, and histopathologic changes exhibited by both groups of patients with MGD.

The overall findings strikingly illustrate that the functional deficit elicited by the abnormal gonadal development in MGD is expressed as incomplete production and/or action of the Mullerian inhibiting hormone (MIH) and T, with concomitant incomplete inhibition of Mullerian development and an impaired differentiation of the Wolffian duct derivatives and external genitalia, thus resulting in a marked asymmetry of the internal and external genitalia. The 14 mosaic patients presented marked phenotypical and histopathological sim- ilarities irrespective of the proportion of cells lacking or having a structurally normal or abnormal Y chromosome. All 14 cases had uterus, Fallopian tube, and epididymis and in 3 of them a vas deferens was also found on the testicular side. The finding of Wolffian derivatives in the streak side of 5 cases suggests either that the in utero production of T by the contralateral testis was adequate to induce some Wolffian duct differentiation in both sides or that the embryonic streak produced margi- nal but sufficient amounts of T or its androgenic pre- cursos to allow some ipsilateral development of Wolffian derivatives [Judd et al., 19701. Conversely, in the 2 cases exhibiting both Fallopian tube and epididymis on the testicular side (cases 7 and 141, a more severe defect in the production and/or action of MIH than that presented by the patients without this Mullerian derivative may be postulated.

The elevated baseline levels of serum gonadotropins in all postpubertal cases indicated the existence of an impaired testicular function of variable degree. In fact, a wide spectrum in T production and reserve was observed, ranging from severe (case 7) to mild (case 1) or minimal (case 5 ) Leydig cell dysfunction (cases 1 and 5). The presence of severe external genital ambiguity in all patients, including cases 1 and 5 who presented almost normal virilization at puberty, suggests that even in those cases with minimally impaired T production, the amount of this androgen produced in utero (particularly between the 8th and 12th weeks of gestation) was insuf- ficient to promote, via 5ct-dihydrotestosterone, a com-

Mixed Gonadal Dysgenesis 267

plete differentiation of external genitalia. Thus, in con- trast to the normal testis, in MGD the ability of the dysgenetic testis to virilize a t adolescence can not be taken as a recapitulation of its capacity to masculinize the external genitalia in utero. With the exception of case 13, all prepubertal cases exhibited normal serum levels of both gonadotropins; the presence of a dysgenetic testis possessing some residual function might ex- plain this finding, particularly considering that during infancy the negative feedback involving the gonads and the hypothalamic-pituitary axis operates at a high sen- sitive level [Conte et al., 19751.

This study confirms and extends previous reports [Davidoff and Federman, 1973; Donahoe et al., 1979; Kofman-Alfaro et al., 1981; Robboy et al., 1982; Wallace and Levin, 19901 and indicates that in most patients with MGD the hormonal profile does not correlate with the clinical, cytogenetic, and histopathological characteristics of the disease. Further elucidation on the specific structural abnormalities involving the testis-determining gene on the Y chromosome in patients with MGD and which almost invariably lead to an incomplete differentiation of the somatic sex structures, will un- doubtedly allow a better understanding of the mechanisms responsible for the wide heterogeneity characteristic of this particular disorder.

ACKNOWLEDGMENTS This study was supported by the Rockefeller Founda-

tion (New York, NY) and the Special Programme on Research, Training and Development in Human Repro- duction, WHO (Geneva, Switzerland).

REFERENCES

Davidoff F, Federman DD (1973): Mixed gonadal dysgenesis. Pediatrics

Donahoe PK, Crawford JD, Hendren H (1979): Mixed gonadal dysgenesis; pathogenesis and management. J Pediatr Surg 14:287-300.

Judd HL, Scully RE, Atkins L, Neer RM, Kliman B (1970): Pure gonadal dysgenesis with progressive hirsutism. N Engl J Med

Kofman-Alfaro S, Perez-Palacios G, Medina M, Escobar N, Garcia M, Ruz L, Mutchinick 0 (1981): Clinical and endocrine spectrum in patients with the 45,X146,XY karyotype. Hum Genet 58373-376.

Robboy SI, Miller T, Donahoe PK, Jahre C, Welch W, Haseltine FP, Miller WA, Atkins L, Crawford JP (1982): Dysgenesis of testicular and streak gonads in the syndrome of mixed gonadal dysgenesis. Hum Path01 13:700-716.

Rutgers JL, Scully RE (1987): Pathology of the testis in intersex syn- dromes. Semin Diagn Path01 4:275-291.

Ulloa-Aguirre A, Chavez B, Mendez JP, Saavedra D, Perez-Palacios G (1988a): Inherited impairment of nuclear androgen uptake as a cause of familial androgen insensitivity. Eur J Obstet Gynecol &prod Biol 28:317-329.

Ulloa-Aguirre A, Mendez JP, Dim-Shnchez V, Altamirano A, Perez- Palacios G (1985): Self-priming effect of luteinizing hormone- human chorionic gonadotropin upon the byphasic testicular response to exogenous hCG. I. Serum testosterone profilp. J Clin Endocrinol Metab 61:926-932.

Ulloa-Aguirre A, Mendez JP, Gonzalez-Castiilo A, Carranza-Lira S, Gana-Flores J, Perez-Palacios G (1988b): Changes in the responsiveness of luteinizine hormone secretion to infusion of the ooioid

52:725-742.

282~881-885.

antagonist naloxone "throughout male sexual maturation. 'Clin Endocrinol (0x0 29:17-28.

Wallace TM, Levin HS 11990): Mixed gonadal dysgenesis. A review of 15 patients reporting single cases of malignant intratubular germ cell neoplasia of the testis, endometrial adenocarcinoma and a complex vascular anomaly. Arch Pathol Lab Med 114:679-688.

Winter JSD, Hughes IA, Reyes FI, Faiman CH (1976): Pituitary-gonadal relations in infancy: 2. Patterns of serum gonadal steroid concentrations in man from birth to two years of age. J Clin Endcrinol Metab 42:679-686.

Conte FA, Grumbach MM, Kaplan SL (1975): A diphasic pattern of gonadotropin secretion in patients with the syndrome of gonadal dysgenesis. J Clin Endocrinol Metab 40:670-674.

mixed gonadal dysgenesis: clinical, cytogenetic, endocrinological, and histopathological findings in...

Documents