VAGINAL
BLEEDING
IN GONADAL
DYSGENESIS
Stephen Kaufman, M.D.
Department of Pediatrics, University of California-San Francisco Medical Center, San Francisco, California
Ftc. 1. Case 1 at 12% years (without therapy).
(Submitted February 3; accepted for publication March 29. 1965.)
ADDRESS: Department of Pediatrics, University of California-San Francisco Medical Center, San
Francisco 22, California.
26
PEDIATRICS, Vol. 37, No. 1, Part I, January 1966
S
POBADIC CASES which probably representovarian dysgenesis have been described since the first decade of the twentieth c’n-tury. This syndrome was first thoroughly described, however, by Turner in 1938,1
when he reported 7 females with short sta-tune, cuhitus valgus, webbed neck, and sexual infantilism. Since that time, the lit-erature has been replete with cases which represent variations of this syndrome. A review of all published cases which are called “Turner’s syndrome” includes
pa-tients who are of either 2 short or of
average height,4 with or without cubitus valgus and pterygium colli,” and who may be sexually immature or sexually mature and fertile.6 Chromosomal studies suggest
an abnormality which involves the
X-chromosome,’5 although even this may not be constant.
This paper presents two unusual cases of females with several of the physical stig-mata associated with Turner’s syndrome. These are the fourteenth and fifteenth pa-tients reported in the world literature who
have been studied by chromosomal karyo-typing that have both the physical stigmata of Turner’s syndrome and repeated spon-taneous episodes of vaginal bleeding.
CASE REPORTS
CASE 1, whose parents were 35 and 38 years old,
was born at term, weighed 5 lb 14 oz and was
17 inches long. By contrast, the birth weight of
her 2 siblings was 7 lb 8 oz and 9 lb 10 oz.
Lymphedema of the extremities was noted in the
newborn period and a slight puffiness of the
dor-sum of the hands and feet still persists. Psoriasis,
diagnosed at age 3, is still active and a mild
hear-ing deficit, first noted at the age of 4 years, also
persists. Although growth velocity is normal, her
height has remained below the 3rd percentile.
s’Ienarche, without other secondary sexual
char-acteristics, occurred at 11 years 11 months and
vaginal bleeding, lasting from 3 to 4 days, with 1
to 2 pads per period, has persisted at monthly
intervals since then.
On physical examination at 12h years she was a
short stocky child with a masculine habitus (Fig. 1), a height of 49% in., weight 68% lb, span 48%
in., upper segment 26%, lower segment 23%, ratio
1:13; blood pressure: right arm supine 115/85;
left leg prone 125/80; pulse 80, respirations 18.
Pertinent positive physical findings included a high-arched palate, 12-year molars on the left but
not on the right side, and a mild bilateral hearing
loss. The neck was minimally broadened at the
base with a low posterior hairline. Pectus
ARTICLES 27
tissue was palpable. The nipples were infantile but
not widely spaced or inverted. The external
geni-talia were immature except for a slight rugation of the labia majora. Pubic and axillary hair was
absent and the clitoris was not enlarged. There
was mild cubitus valgus bilaterally, with
fore-shortening of the fourth and fifth knuckles on the
left hand and the fifth knuckle of the right hand.
The third and fourth toes of both feet were
ab-normally short and webbed at their bases. There
were multiple pigmented nevi on the skin, active
psoriatic lesions, and healed scars from past lesions.
On three occasions, buccal smears stained with
orscein revealed between 15 and 17% Barr bodies/
100 cells (normal values in our laboratory: less
than 4% for males; more than 20% for females).
Peripheral blood smears demonstrated 8
drum-sticks/500 neutrophils in our patient and 7/500
in her mother.9 Karyotyping showed 45
chrorno-somes in all 30 cells counted, with an XO
idio-gram in each of 5 cells. In a second chromosomal
count 1 year later, 45 chromosomes in all 50 cells
counted and idiograrns of 15 cells were consistent
with an XO pattern. A chromosomal count on the
mother showed 46 chromosomes in 28 out of 30
cells, with idiograms of 2 cells yielding an XX
pattern. The father and the siblings were
unavail-able for study.
FSH was positive at both 5 and 80 mouse units,
urinary estrogens were negative at 3 and 1 ?% and
a vaginal smear at approximately mid-cycle was
negative for estrogen effect. Urinary
17-hydroxy-corticosteroids were 4.0 mg/24 hr and 17
keto-steroids were 1.4 mg/24 hr.
Because of the known relationship between
ovarian dysgenesis and
pseudopseudohypoparathy-roidism, investigation of the serum calcium and
phosphorus and the renal tubular response to
para-thyroid extract was undertaken. Serum calcium was
10.5 mg/100 ml, serum phosphorus 4.3 mg/100 ml,
alkaline phosphatase 14 SJR units, total proteins
7.0 gm/100 ml. Following intramuscular injection
of 500 units of parathormone (Lilly) every 12 hours
for 4 doses, serum calcium rose to 15.5 mg/100 ml,
serum phosphorus fell to 3.4 mg/100 ml, and
alka-line phosphatase to 10 SJR units.
X-ravs revealed a disproportionate shortening of
the fourth and fifth metacarpal of the left hand
and the fifth metacarpal of the right hand, with
fusion of the epiphysis typical of
pseudopseudo-hypoparathyroidism rather than Turner’s syndrome.
Beaking of the middle aspect of the tibial
meta-physis was present bilaterally with an inclination
of the medial epiphyseal cartilage typical of Turn-er’s syndrome. The third and fourth metatarsals showed premature closure of the epiphyses, and
bone age was equivalent to the chronological age.
Estrogen therapy was inaugurated just prior to
the patient’s thirteenth birthday. In the subsequent
6 months she grew 1.75 in. and gained 8 ib;
bud-Fic. 2. Case 2 at 2 ears.
ding of breasts and pigmentation of the nipples
occurred, and the body habitus became more
feminine. Periodic vaginal bleeding has continued
and at the present time is more profuse. Sexual
hair has appeared and occasional acneiform lesions
have been noted.
CASE 2 was born of a pregnancy complicated
by maternal hyperemesis. The parents were 36
and 38 years old at the time of her birth, which
was 2 weeks prior to term. Her birth weight was
4 lb, 13 Oz; the height was unrecorded. Mild
lymphedema of the distal extremities and bilateral
ptosis were noted in the nursery. The posterior
fontanelle did not close until 14 months and the
anterior fontanelle was still widely patent at 2
years. At 2 years she was below the 3rd percentile
in height and weight, with pinched facial features,
a short frenulum, bilateral ptosis and hyperopic
astigmatism (Fig. 2). Laboratory studies suggested
normal thyroid function and normal intelligence;
gonadotropin assays were negative; bone age was
1 year retarded and an electroencephalogram
dem-onstrated a generalized irregularity.
At the age of 13 she was seen because of her
short stature. The intervening 1 1 years had been
complicated only by 2 nocturnal grand mal
seiz-ures. Vaginal bleeding occurred for the first time at age 13 and has continued irregularly
approxi-mately every 2 weeks since then with a moderate
flow for 5 to 7 days accompanied by mild
ab-dominal cramping and weakness. When she was 14
Ftc. 3. Case 2 at 14 years.
On physical examination at age I 4, she was
52% in. tall, weighed 67 Ib, had a blood pressure
of 120/80, pulse 84, and a head circumference of
20 in. A pinched facies and bilateral ptosis gave
her a dull vacant expression. The cars were small
and low-set with abnormally narrow external
audi-tory canals. The palate was high arched, the teeth
irregularly placed, and the mandible recessed. Her
neck was short, mildly webbed, with a low
pos-tenor hairline (Fig. 3). Her chest was
shield-shaped with widely spaced hut not inverted nipples and without palpable breast tissue. A small
amount of straight black pubic and axillary hair
was evident; mild cubitus valgus was present; the skin was dry and several raised brown nevi were apparent.
Follicle-stimulating hormone levels were
border-line at 160 mouse units, positive at 80; vaginal
smears for estrogen effect produced 38% basal,
60% intermediate and 2% superficial cells. Buccal
smears were consistently positive and a chromo-somal count revealed a mosaicism of 16 cells with 45 chromosomes and 37 cells with 46. Idiograms
suggested an XO/XX mosaicism. The bone age
was between 11 and 13 years at a chronological
age of 13 years, 6 months, and the abnormal
knuckle sign associated with gonadal dysgenesis was present.’#{176}An electroencephalogram revealed
an inactive focus in or deep to the left temporal
region . w\’ith the institi itioii of estrogen tllIral)\’
breast buds Ll)Pet1rel within 1 month; 2 months
later, site refused all medications and has
con-tiflu((l to do so until the l)rcsetlt time. At 14 ears,
6 months she weighed 74 Ibs, was 53 1/16 in. tall,
had luxuriant pubic and axillary hair and scanty
vaginal bleeding at monthly intervals which lasted
7 days without dysmennorhea.
REVIEW OF THE LITERATURE
Prior to the development of the tech-niques for interpreting buccal smears for sex chnomatin and chromosomal karyotyp-ing, the diagnosis of ovarian dysgenesis with vaginal bleeding was difficult to make with certainty. Available data listed in the
table suggest that the first 20 cases (in-cluding our 2 cases) are highly probable examples of the syndrome, whereas the evidence is not as conclusive in the remain-ing cases. Several other vaguely
docu-mented cases have been reported but are
ARTICLES 29
cases reported by Bahner, Haddad,’4 Lem-ii,” and Lindsten.15 With the exception of our Case 2, Haddad’s Case 3,14 and Lind-sten’s Cases 51, 53 all other patients with mosaic karyotypes
XX/XO,
XX/XXX/xO,
and XO/XY have been amennorheic. There have been 4 reports of pseudopseudo-hypoparathyroidism with ovarian dysgene-sis-1 case by Archibald’o and 3 by WenifTen “ None of these had
chromo-somal analysis or investigation of the re-sponse of the renal tubule to parathynoid hormone.
The table shows the wide variation of physical and laboratory data reported in these patients. Several had no evidence of cubitus valgus or ptenygium colli, some were of average height, 2 had normal breast de-velopment, 1 was fertile, 2 had positive buc-cal smears for sex chromatin, and 1 had a
normal excretion of gonadotropins.
COMMENT
Our report describes the fourteenth and fifteenth cases in the world literature of patients with ovarian dysgenesis and ne-peated spontaneous episodes of vaginal bleeding who have had chromosomal karyo-ty ping. The usual order of sexual maturation was disrupted; both girls had vaginal bleed-ing prior to the onset of sexual hair or
changes in the breasts and nipples. With the
institution of exogenous estrogen therapy, breast buds quickly became visible and palpable but a normal degree of mammary tissue has not occurred yet. The etiology of the underdevelopment of the mammary tissue is not clean. We are investigating the possibility that minute amounts of
circulat-ing estrogen during childhood can prime
the mammary tissue for more adequate re-sponse during puberty.
Case 1 reveals a 45
XO
chromosomal karyotype without evidence of mosaicism in the lymphocytes; however, the presenceof 15 to 17% Barr bodies in the buccal smear, a figure compatible with previously described patients with mosaicism, and a
chromatin pattern of 8 dnumsticks/500
neu-trophils, strongly suggests mosaicism. The
mother, with a typical 46 XX chromosomal
karyotype, has the same percentage of
drumsticks, further emphasizing the likeli-hood of mosaicism in our Case 1. Our in-ability to demonstrate two or more differ-ent chromosomal cell lines may be due to our present inability to culture other tissues.
Pseudopseudohypopanathyroidism and
ovarian dysgenesis may both exhibit
abnor-malities of the fourth metacarpal, short sta-tune, and a tendency to reduced intelli-gence. The cases of Werf Ten Boschl2 and Archibald0 suggest that this relationship
may not be entirely fortuitous. Further-more, the response of the renal tubules to parathyroid hormone becomes important if we consider the current theory that pseudo-and pseudopseudohypoparathyroidism are
part of the same continuum of disease.28
Our Case 1 had shortened fourth and fifth
metacarpals of the left hand, a shortened fifth metacarpal on the right hand, and foreshortened third and fourth metacarpals bilaterally. Radiologically, these bones are typical of
pseudopseudohypoparathyroid-ism rather than ovarian dysgenesis (Fig. 4) for the following reasons. In Turner’s syn-drome the metacarpals tend to be normally shaped with a normal or retarded fusion of the epiphysis and minimal degree of
short-ening of the fourth metacarpal. In pseudo-pseudohypoparathynoidism the abnormality
often involves the first and fifth metacarpal as vell as the fourth, which is abnormally broadened and significantly foreshortened, with a premature closure of the epiphysis
and lack of normal 2930
Since the patients described by Werif Ten Bosch” and Archibald’#{176} had normal levels of serum calcium and phosphorus and the renal tubular response to parathyroid hormone was not tested in them, investiga-tion of the calcium and phosphorus
. Ct I -;;‘e . 2; ,-I -. C12
---:
#{149},t_
cI)...1 -‘ ... , Cl, .:
a?-&).c -e
,, . #{176} &f3 -.
t
‘-t:
-e.fi -4 .‘ o, ©* ‘‘- --: 4
i
. ::‘.-I.
u,-ae ,% :_..Cl C) .. CI b uz
.. Ct tez
C) ‘ .. cI u d , t) ‘ .. c tez
: .. c uz
.. c ez
.:: . C “ =ca 4-e 2? , “ .. to’ e te. L u dz4z
:
tL -.zz
z
z, - f-. Cz
4. -Cz
4 4 , 4... .
*
.)
a., +
‘..
+.©
a + + + ©
©+
++ © © + + +
+©
©© + -.L-r.-f-’ 0z
-Cz
C a C ) fi .. C -C Cz
C C C,-.‘ ,
‘-‘.a
p -c’ C CC ,.L . j #{149} ‘ .2 : s+;
, -e 4 C’ -‘ 2? n ‘ -C . -C . . ‘ -“ nt k ‘;_
--e C C . . , c!
-e C .!
.- . .C..‘.‘. -;.fi Z 2) C C C C-z
-Ct , C C = . Z C C ..-a )., : ‘f3 -e2’2
k3
&e3 e3
-i-’ -e ‘
&n y’ C
“
C -‘
)
‘ ,..
. ..? .-‘- - -. C 2’2 C’2
C
‘-©
e1 4 2’2
-C’ 2’2 - -) -t..
-- - 4 2’2 - t 8’ ‘3 - c &f
‘3, a , ,--
-z
C: CONADAL DYSGENESISC C ..-. c
ARTICLES
7 I, C -;C ...C. CC ‘; C c.I
z . Cz
.C. C© aC C -. bC a . ) C QJ L,D L:) tC ; e aCE
“‘ u.c a ., E.za $.CC a a a C -4 31 .‘I
z
a 4’ 0 a C. C C C a .tt a a .-a ,C
---a a.’3 -5)Z ;-z .-;
C-z .: ;Lz
z
z
zzz
z
z
,: . N
.“r
.:,2 5) .i ,4-z
‘. 4- 4-. . . 4- 4- 4.- 4-. 4-..
4-© + + “. C: ©©© + © + +
E
C: H + + + © + --L ‘. ‘H’
iz
L Lz
L L -fi ,? ‘ #{149}Ii , C . :--a a:t ,__C --:c; .-;:‘ C t -zc ‘3 tr C’ _ ‘‘ a a 31D9 . C ,.2
‘. z .-a > ‘ a , C.,,;r
- -j ‘3’--.2
C ‘ CC --‘ CE
-C ,, C -‘ C ‘-‘z C Z ‘!Z
5)
Ii
Z .4C’ ‘3j..:
‘ . 4C’ SC kf5 -5t
-*IC’“3 0‘3 ..
C’ C: “3 ..IC’ ‘t “3 -IC’ ‘2
,f: t-‘2 ‘3
;-z.
5)-,a ‘3’ , t.-54 . , ©2’) - c-
--K’ ‘3?
- -
-- - - - ,- - - - ‘3’ - 5’3 - ‘3
‘3’ 5)3
‘3’ ‘34
“3 50 N
‘5’ ‘54 ‘3? ‘3)
C
a‘ a
Ftc. 4. The foreshortening of the fourth metacarpal (Case 2) is demonstrated by the line which connects
the distal epiphysis of the fifth, fourth, and third metacarpals. In the normal hand, a line from the fourth and fifth metacarpals would not touch the third. The differences between the metacarpal abnormality in ovarian dysgenesis as opposed to
Patients with
pseudopseudohypoparathy-roidism have 46 chromosomes with a nor-mal karyotype,3’ suggesting that if there is
a genetic relationship between the two syn-dromes it is more subtle than our present
chromosomal evaluation techniques can demonstrate.
Case 2 is clearly a chromosomal mosaic and is unusual because of the physical re-semblance of the mother and daughter. The
sudden death of the mother of an aontic
aneurysm, an anomaly occasionally seen in
Turner’s syndrome, raises the possibility of
an inherited chromosomal aberration.
SUMMARY
Two cases of ovarian dysgenesis with pe-riodic vaginal bleeding are presented, with evidence which suggests chromosomal
mo-saicism. In a review of the world literature
our cases are the fourteenth and fifteenth
described with vaginal bleeding and
chromosomal analysis. Our first case also demonstrates the foreshortened metacarpals
of pseudo- and
pseudopseudohypoparathy-is dpseudopseudohypoparathy-iscussed in text.
noidism. It is the fourth case reported with ovarian dysgenesis and brachymetacarpal dwarfism and the first in which renal tubular sensitivity to parathynoid hormone has been determined. It is suggested that the clinical
term, Turner’s syndrome, be replaced by a
classification based on chromosomal karyo-type.
ADDENDUM
Rothenbuchner et al. (Human
Chromo-some Newsletter, 14:20, 1964) report a 17-year-old girl, 132 cm tall, 31 kg, with poor breast development, no sexual hair and no physical stigmata of ovarian dysgenesis who had one episode of vaginal bleeding. Sex chromatin studies revealed 4% Barr bodies and a chromosome count of 45/46 XO/XX in the blood and 45/46/47 XO/XX/XXX
in the fibroblasts.
REFERENCES
1. Turner, H. H.: Syndrome of infantilism,
con-genital webbed neck, and cubitus valgus.
Endocrinol., 23:566, 1938.
ARTICLES
33 A. M., and Eberlein, W. R. : Turner’ssyn-drome in the male. J. Pediat., 58:321, 1961.
3. Fraccaro, M., Ikkos, D., Lindsten, J., Luft, R.,
and Tillinger, K. G.: Testicular germinal
dysgenesis (male Turner’s syndrome). Report of a case with chromosomal studies and
review of the literature. Acta Endocr., 36:
98, 1961.
4. Engstrom, W. W., and Stoddard, F. J.:
Con-adal dysgenesis : Ovaries in association with
chromatin-negative pattern in somatic cells.
Metabolism, 20:780, 1960.
5. Hoffenberg, R., Jackson, W. P. U., and Muller, W. H.: Gonadal dsgenesis with
menstruation: Report of 2 cases. J. Clin.
Endocr. Metab., 17:902, 1957.
6. Bahner, F., Schwartz, G., Heinz, H. A., and
Walter, K.: Turner syndrome with fully
developed secondary sex characteristics and
fertility. Acta Endocr., 35:397, 1960.
7. Becker, K. L., Sprague, R. G., and Albert, A.:
Chromosomal spectrum of gonadal
dysgene-sis. Mayo Clin., 38:490, 1963.
8. Parsons, L., and Sommers, S. C.: Gynecology,
Philadelphia: W. B. Saunders, 1962, p. 65. 9. Murthy, M. S. N., and von Haam, E. : The
occurrence of the sex chromatin in white
blood cells of young adults. I. Study of normal peripheral blood. Amer. J. Clin.
Path., 30:216, 1958.
10. Archibald, R. M., Finby, N., and de Vito, F.:
Endocrine significance of short metacarpals.
J. Clin. Endocr. Metab., 19:1312, 1959. ii. Lemli, L., and Smith, D. W. : The XO
syn-drome: A study of the differentiated
pheno-type in 25 patients. J. Pediat., 63:577, 1963.
12. Stewart, J. S. S.: Gonadal dysgenesis: the genetic significance of unusual variants. Acta
Endocr., 33:89, 1960.
13. Bricaire, H., Tourneur, R., Leprat, J.. and de Gennes, L. : Gonadal dysgenesis with
pseudo-menstrual genital hemorrhages.
Apropos of 3 personal cases. Presse Med., 69:425, 1961.
14. Haddad, J. G.: Turner’s syndrome: Case
re-ports and review of clinical and cytogenetic
aspects. Bull. Tulane Med. Fac., 21:139,
1962.
15. Lindsten, J.: The Nature and Origin of Chromo-some Abberations in Turner’s Syndrome, Stockholm, Almquest and Wiksell, 1963. 16. Guisti, C., Borghi, A., Begozzi, V., and
Toe-cafondi, R.: Rass. Neurol. \Teg., 15:253, 1960.
17. Varney, R. F., Kenyon, A. T., and Koch, F. C.:
Association of short stature, retarded sexual
development and high urinary gonadotropin
titers in women: Ovarian dwarfism.
J.
Clin. Endocr. Metab., 2:137, 1942.18. Lisser, H., Curtis, L. E., Escamilla, R. F., and
Goldberg, M. B. : Syndrome of congenitally
aplastic ovaries with sexual infantilism, high
urinary gonadotropins, short stature and other congenital abnormalities. Tabular pre-sentation of 25 previously unpublished cases. J. Clin. Endocr. Metab., 7:665, 1947. 19. Albright, F., Smith, P. H., and Fraser, R.:
Syndrome characterized by primary ovarian
insufficiency and decreased stature. Report of 1 1 cases with digression on hormonal control of axillary and pubic hair, Amer.
J.Med. Sci.,204:625, 1942.
20. Briggs, D. K., and Kupperman, H. S. : Sex
differentiation by leukocyte morphology.
J.
Clin. Endocr. Metab., 16:1163, 1956. 21. Perloff, W. H., Stein, R. 0. : Stigmata of
Turner’s syndrome in woman with regular
menstrual rhythm, J. Clin. Endocr. Metab.,
13:1548, 1953.
22. Werif Ten Bosch, van der: The syndrome of
brachymetacarpal dwarfism
pseudo-pseudo-hypoparathyroidism) with and without
go-nadal dysgenesis. Lancet, 1 :69, 1959.
23. Michelin, R. : Le syndrome de Turner-Albright.
Rapport de deux case. These de Paris, 1949,
No. 417, quoted in La Presse Medicale 69:
427, 1961.
24. Netter, A. : Fonction endocrine der testicule.
Paris: Mal Masson, 1957.
25. Guinet, P., and Putelat, R. : Le syndrome de
Turner. Vie Med., 37:441, 1956.
26. Perrault, M., Klotz, B., and Housset, E. : Deux
cas de syndrome de Turner avec
surdi-mutite dans une meme fratrie. Bull Mem. Soc. Med. HOp. Paris, 67:79, 1951.
27. del Castillo, E. B., and Argonz,
J.:
Syndromeof rudimentary gonad: Report of four cases with unusual alterations of the gonad. Acta Endocr., 24:379, 1957.
28. Cordan, C. : Introduction, Year Book of
En-docrinology, 1960-61, Chicago: Year Book
Publishers, 1961, p. 5.
29. Steinbach, H. : Personal communication, 1964.
30. Kosowicz, J.: Changes in the medial tibial condyle: A common finding in Turner’s syn-drome. Acta Endocr., 31:321, 1959. 31. Schwarz, C., and Walter, K.: Chromosomal
analysis in gonadal dysgenesis with
pseudo-pseudohypoparathyroidism. Lancet, 1:1075,
1962.
Acknowledgment