PSEUDOHERMAPHRODITISM
WITH
MULTIPLE
CONGENITAL
ANOMALIES
Report
of a Case
By Edgar J. Schoen, M.D.,* Alexander L. King, M.D., A. LaMont
Baritell, M.D., and William F. Knigge, M.D.
CLINICAL
NOTES
H
ERMAPHIiODITISM, as reviewed in theexcellent monograph by Hugh
Young,’ was known to the ancient Hebrews
audI Greeks. In spite of the early
recogni-tion of this syndrome and the many inter-esting case reports in the literature
(Neu-gebauer in 1908 noted over 1200
indivi-dual cases of hermaphroditism), the etiol-ogy tfldi classification of the various types
of hermaphroditism have never been
corn-pletely agreedi upon.
Within recent years the role of congenital
adirenal hyperpbasia in the causation of the
syndrome of female
pseudohermaphrodit-islil has been well established,’’ 15 but the factors involved in the etiology of male pseudlohermaphnoditism and true
hermaph-roditisrn are still in doubt. The
impor-tance of both zygotic and hormonal factors
in sex differentiation has been demon-stratedi IJy a wealth of experimental data.31’
Accompanying the many theories of sex
differentiation have been a number of
proposed classifications of
hermaphrodit-The simplest andi most popular
classification today is the division of her-maphrodites according to gonadal sex. Thus, a true hermaphrodite has germinal cells of 1)0th sexes. Pseudohermaphrodites have the
gonads of only one sex but their external
genitalia are such as to cause doubt as to
true sex; male pseudiohermaphrodites hav-ing testes andi female
pseudohermaphro-dites ovaries. Although exploratory
laparot-omy is still necessary for final diagnosis of
From the l)epartments of Pediatrics, Surgery
and Urology, Kaiser Foundation Hospital,
Oak-Iind, California.
OADDRESS: 280 MacArthur Boulevard West,
Oakland 11, California.
male pseudohermaphroditism and true
hermaphroditism, the elevated urinary
17-ketosteroid excretion in combination with
typical genital anomalies usually obviates the need for operation in female
pseudo-hermaphroditism. Recently methods have been described for determining
chro-mosomal sex by skin biopsy2#{176} and blood
2 1 These chromosomal studies may prove to be of considerable aid in the
diag-nosis of hermaphroditism butthey have not yet eliminated the need for exploratory
laparotomy.
In contrast to hermaphroditisrn the
syn-drome of ovarian agenesis has been recog-nized only comparatively recentby.”’
Al-though abnormalities of the genital system (female sexual infantilism) in combination with other congenital anomalies make tip the syndrome, in the cases previously
tie-scribed there has been no doubt as to sex. “Turner’s syndrome” has been described in
both males and females, but none have been pseudohermaphrodites.
The present report describes a case con-sidered to be male pseudohermaphroditism
in combination with other congenital
anomalies. Most of the congenital anomalies present in this patient have previously been
described in the syndrome of ovarian agen-esis but the authors are unaware of any report of a similar case.
History
REPORT
OF
A CASE
M.G., an 1 1%-year-old white “female,” was
admitted on August 23, 1954, and discharged on September 18, 1954. She was referred for
364 SCUOEN - PSEUDOHERMAPHRODITISM
approximately 7 pounds at birth. There was no neonatal distress. At birth it was noted that she
Ila(1 l’cUIlitr genitalia and an abnormally
shaped head. She was considered to be a
fe-male
and
was reare(l as a girl. Growth and(lcvvlopnleil t were grossly ttormal. The patient has never had convulsions, but there is a
his-tory of occasional frontal headaches. She wears glasses to correct au eve niuscle weakness.
She has been tinted! to be almost completely (leaf in the right ear.
i’here is no family history of sexual
anoma-lies 01 other coulg(uuital ailoinalies.
Fin. I. An I lh-vear-old male i)sct1ohertii:ip1iro-(lite. Note the stock bod l jId, short phallus, (111(1 lnoruuially Slhtj)cd head.
Physical Findings
The child is a vell-deveIoped and well-nourished, blonde, white “female.” The body build is stocky. neither typicaII’ masculine nor feminine (Fig. 1
)
with accentuation of thebum-bar curve. Temperature, normal; pulse, 84;
res-pir1ti1i, 20/mm. ; 1)bood pressure, 1 16 ‘80; height, 54 inches (15th percetitile), and
weight, 80 Potindls (50th percettile). The head is abnormally slia1wcl, there being a decreased anteroposterior diameter and flat-tening of the supraorbital ridges. giving her eyes an excessive irnii11euice. No hirsutism or abnormal pigmentation was seen
on the skin. The eyes showed an alternating
esotropia ; ophthalmoscopic examination was normal. A complete percepti’e deafness was
presetit in the right ear. The neck appeared
short Iflit there was uio ‘ebbing. iliere was no evidlence of breast development. Examination
of the genitalia (Figs. 2 anl :3) showed a
plial-Ins, 1 .5 cm. iii leiigth, which had the
(IP1)ear-aitce of a clitoris. The urethra was 1)asterior to the plitlItus. There was no scrotum or labia,
auirl ho vaginal opening or dlifliple in the
median ra1)he between the urethra and the auiiis. No l)erineal or inguinal masses were
pal-1)7tbk. On rectal examination no I)r5ttte,
cervix, or adnexae could1 be felt. Citbitus valgus
vas not present.
Laboratory Findings
Urine an(l complete l)bOOd count were nor-nial. Boentgenograms: The chest and pelvis
were normal. PeIograms were normal. The dorsal ali(l lumbar spine showed a sl)iIi bifida
occtilta at the level of L-5 and S-I
.
The wristshowed a bone age of 7 years 10 months (Todd
Standards) as compared vith a chronological
age of 1 1% years. The skull (Fig. 4) shoWedb a
congenital abnormality of shape with the so-called ‘steeple frontal area. The calyarium had prominent convolutional markings. The
sella turcica was increased in size and depth,
without actual destruction, but with some
thinning of the dorsum sellae.
Audiometry revealed almost cimplete per-ceptive deafness on the right, most marked in the higher tones. There was also diminished
perception of higher tones on the left. An in-sulin tolerance test (0. 1 unit kg. intraveili)usly)
was normal. Serum protein-bound iodine was
excre-CLINICAL NOTES 365
demonstrating the small phallus, pigmeation on
either side of the median raphe, and absence of scrottini.
or structures grossly resembling
could be felt.
corpora cavernoa
tion#{176}on 3 occasions showed values of 3.2, 2.1
and 1.9 mg./24 hr. (normal 2-8 mg./24 hr. for
this age). The 17-hydroxycorticosteroids#{176} on 2
occasions were 4.9 and 4.1 mg./24 hr. (normal
4 to 13 mg.24 hr.). Fifteen units of a standard
titered 1)atch of ACTH (supplied by Dr. P. Forsham) caused the 1 7-hdroxycorticosteroid
excretion to rise to 12.4 mg./24 hr., a threefold
rise, which is considered to be a normal
adlrenocortical response.23 24 A gonadotropic
hormonef assay showed values of less than 5
mouse units; an estrogenf assay showed values of less than 2 g. 24 hr. (estrone equivalents). (Both are within normal limits for either boys
O Determinations of urinary 17-ketosteroids and
17-hydroxycorticosteroids were performed at the
University of California Metabolic Laboratory
through tile courtesy of Dr. Peter Forshani using a
modification of the Callow-Callow-Emmen
reac-tion for the l7-ketosteroids and a niodified
Porter-Silber technique for the 17-hydroxycorticosteroids.”
I Estrogen and gonadotropic hormone determina-tions were performed at the University of
Cali-fornia Gynecology Endocrine Laboratory.
or girls of this age group.)
Urethroscopic examination revealed that the
urethra had the appearance of a male urethra
with a structure like a verumontanum in the
region of the apex of the prostatic urethra.
No sinuses or openings into the urethra could be seen and the bladder and ureteral orifices appeared normal.
Using the technique described by Moore
et al.,2 a skin biopsy was taken for determina-tion of chromosomab sex. This was reviewed by Dr. Jackson Crane (University of California Department of Pathology) who found that 5 per cent of the cells had “chromatin bodies,” a count considered characteristic of male chromosomal sex.2#{176}In addition a blood smear examination was carried out at this hospital (Dr. N. L. Morgenstern) according to the tech-nique described by Davidson and Smith2’ and only 1 questionable chromatin structure was seen in more than 300 polymorphonuclear Ieu-kocytes, a count also considered indicative of male chromosomal sex.
in-SCHOEN - PSEUDOHERMAPHRODITISM
Fin. 4. Roentgenograni of the skull, showing the oxycephaly, with “steeple” frontal
area, hammered silver” appearance and ballooning of the pituitary fossa.
telligence intid’1it vas estimated to be
be-tween 85 ail(i 95. The psychiatrist felt at fiist
that the 1)atwutts 1)sVchOseXUal orientation vas
(h(.’fihiitel\ female. She overcompensateci for bier feelings of confusion al)Out her genitalia by
cx-1’”g ignorance of any genital
abnormali-ties. In later interviews she expressed a great deal of ambivalence regarding her sexual status.
Course
After a joint conference with the several
speciilties involved, exploratory laparotomy was performed. On entering the abdbominal caVity the surgeon saw ilO evidence of a uterus, ovi(iucts or other female internal genitalia. On either side there was a small oval gonad, each
about I .5 cm. in diameter. The one on the left
vas intra-abdoininal, being about :3 cm. al)ove the internal inguinal ring; the one on the right
was fotmd to be lying within the inguinab canal. Grossly, they had the appearance of
small testes, each with a vas deferens. The
substance of the gonad itself on each side was
soft and fatty. Biopsies were taken from both
these organs and the abdomen was closed.
It was felt that adequate biopsy specimens were taken, especially on the right where it
was thought that about a quarter of the gonad was removedl.
The pathology report (Dr. N. L. Niorgen-stern) noted that the specimen from the left
revealedi fat andi fibrous tissue containing a few
veins. There were several small duct-like struc-tures hued by a single layer of tall columnar cells surrounded by a circumferentially ar-ranged smooth muscle coat. This resembled an
epoophoron (Fig. 5). The specimen from the
right (Fig. 6) revealed a loose collagenous matrix inwhich were tul)Ules lined by cuboidal cells with pale-staining cytoplasm. In a few
ar-CLINICAL NOTES 367
FIG. 5 (Upper). Photoniicrograph of specimen from biopsy on the left, which seems to resemble an
epoophoron (see description in text).
368 SCHOEN - PSEUDOHERMAPHRODITISM
rangedi smooth muscle coat slightly thinner than that seen around the structure on the left. The specimen on the right was considered to be an immature epididvmis. The pathologist noted that although there was no tissue present resembling male gonad, the specimens from both the right and tile left represented wobffian dierivatives.
M an agemen t
DISCUSSION
The problem presented is that of an
11%-year-old child, reared as a girl, who shows: 1) hypoplastic genitalia (sex designation
un-certain); 2) complete absence of female in-ternal genitalia on exploratory baparotomy; 3) skin biopsy indicative of “male”
chromo-souiial pattern; 4) gonadls showing the pres-ence of wolffian derivatives, and grossly
resembling testes, and 5) other congenital anomalies.
It is of interest that the majority of cases
of male pseudohermaphroditism reported were reared as females and actually
femi-nized at puberty. It has been known for some
tune that normal adult unabes excrete estro-gen, and there is evidence that the site of
this estrogen formation is in the testis.27
However, it has been considered that in
feminized male pseudohermaphrodites
es-trogen plays an increased role, either due to primary estrogen difference or to a varied
end organ response.2S34
Recently Schneidler et #{252}l.,2)Morris,36 and
Botella-Llusia7 have called attention to
feminization in male
pseudohermaphro-dites. Schneider et al.5 reported 6 cases in
1 family. Morris3 collected 80 cases from the literature, added 2 of his own and
re-ferred to this syndrome as “testicular fem-inization.” Some of the characteristics of
the syndrome as described by both Schneider and Morris were: 1) female body contour; 2) normal female breasts; 3) ab-sent or sparse axillary and pubic hair; 4)
female external genitalia-often underde-veloped labia, small clitoris audi a short blind vagina with no cervix, and 5) gonads which are usually intra-abdominal testes.
There is, in most instances, hyperplasia of
the Leydig cells and absence of
spermato-genesis in the tubules.
This patient did not have the female ex-ternal genitalia reported in these previous
cases except for the small phallus, and since she has not undergone puberty, the female
body contour and breasts remain in
ques-tion.
The robe of psychosexual factors in up-bringing has been increasingly emphasized during the past few years.25’ 26, 30, 38-40
El-lis38 reviewed 84 cases of hermaphroditism from the literature and noted that in the majority of cases the libido and sex robe
corresponded to the sex in which the pa-tient was reared.
Thus, the nature of the external geni-tahia, the psychosexual orientation of this
patient, and the possibility that she might feminize at puberty have bed the authors to feel that she should be continued as a fe-male. If at puberty she masculinizes or remains eunuchoid the present plan is to
administer estrogen with or without surgi-cal removal of the gonads. The ultimate decision will depend upon the
circum-stances at the time of puberty.
Possible Relation to Turner’s Syndrome
When one is confronted with a case in
which genital abnormalities are accom-panied by multiple congenital anomalies of other systems the syndrome of ovarian agenesis, or Turner’s syndrome, comes to mind. The classical triad originally de-scribed by Turner in 193841 consisted of
sexual infantilism, congenital webbed neck and cubitus vabgus. Since that time other
anomalies have been noted to be associated with the syndrome,47 among them being: congenital deafness; ocular abnormalities such as strabismus, coboboma, cataracts, ptosis, and mild exophthabmos; vascular anomalies such as coarctation of the aorta;
bony anomalies such as spina bifida,
re-tarded bone age, genu valgus, osteoporosis, and fusion of cervical vertebrae, and mental retardation. The present case showed
CLINICAL NOTES 369
retarded bone age, short neck (but no
web-bing or fusion of cervical vertebrae), some
shortness of stature and oxycephaly in ad-dition to her genital anomalies.
In 1942, Abbright et al.42 and Varney et al.’ emphasized the importance of elevated
gonadotropins and lack of ovarian function in ovarian agenesis. Although this patient
did not have any gonadotropins demon-strable in her urine this finding is of limited significance because she has not shown evi-dence of puberty as yet. In addition the
cases of Hertz et al.,44 Martin and
Cour-voisier,46 and Dorif et al.5 failed to show elevated gonadotropin excretion in adults.
Since the initial description of the
syn-drome of ovarian agenesis about 100 cases in females have been brought to attention. In 1943 Fbavell9 reported the first case of
what was considered to be “Turner’s syn-drome” in a male. Up to the present time 8 other cases have been reported in males,
the most recent by Prunty et al.8 However,
in the cases of the males in whom biopsy
of the testes were reported, all have shown
gonadal elements, although there is often
hypoplasia, usually of the interstitial cells. No case in the male with complete absence
of germ cells, analogous to ovarian agenesis
in the female, is knowi to have been re-ported. Neither is there a known case of “Turner’s syndrome” in a
pseudohermaph-rodite. The cases of male pseudoher-maphroditism reported in the literature
have been free of any group of congenital
anomalies other than those of the genitalia.
The demonstration of a case in a male
similar to ovarian agenesis in the female has significance regarding the mechanism
of sex differentiation which overshadows its
interest as a simple medical rarity. In this respect, Wilkins and Fleischmann,6
report-ing on 3 cases of ovarian agenesis with com-plete back of ovarian development, stated that “for conclusive proof that sex
differ-entiation is determined solely by zygotic factors it would be necessary to find male
individuals analogous to our patients and
lacking entirely in gonadal development.”
Whether or not the present patient is such
an individual cannot be definitely stated at this time. Final proof would depend upon
the demonstration of total absence of gona-dal tissue in serial sections of both gonads.
SUMMARY
The present paper reports a case of
prob-able male pseudohermaphroditism in combination with multiple congenital anomalies. The management of the case and the possible relationship to “Turner’s syndrome” are discussed.
ACKNOWLEDGMENTS
The authors express their appreciation to Dr. Janet MacArthur and Dr. Nathan B. Talbot, Massachusetts General Hospital, Boston, Massachusetts, for suggestions in the preparation of this paper.
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E.: ACLINICAL NOTES 371
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