Download True Hamartoma of the Hypothalamus Associated with Pubertas

TRUE HAMARTOMA OF THE HYPOTHALAMUS ASSOCIATED
WITH PUBERTAS PRAECOX*
RICHARD B. RICHTER, M.D.t
[Chicago, Ill.]
CLINICAL DATA
The patient was one of a series of six cases of precocious sexual development
recently studied and reported upon by Seckel, Scott, and Benditt (4). The following clinical account is a summary of their history of the case. (Their Case 1).
Rosalie B., weighed 2.25 kg. at the time of her normal, full-term delivery. Her physical
and mental development were normal until she was 2! years of age. It was then noted that
her breasts became unusually large. At 3 years she began to menstruate and soon developed
regular, 28 day cycles. From 2! to 7 years of age her breasts continued to enlarge and her
general body growth exceeded that of other children of her age. There were no physical
abnormalities other than those concerned with growth and sexual development. In particular, there were no indications of hypothalamic or other neurological disease. At 7 years of
age she had the appearance and genital development of a 16 year old adolescent girl. She
measured 147 em. in height and weighed 44.7 kg. Her bodily contours were mature. The
glandular tissue of the breasts was well developed and the nipples were fully formed. Pubic
* Read before the American Association of Neuropathologists, Atlantic City, N. J.,
June 11, 1950.
t From the Division of Neurology of the University of Chicago Clinics.
368
Downloaded from http://jnen.oxfordjournals.org/ by guest on October 29, 2016
The regulatory influence of the nervous system upon such elaborate and complex events in the life of the organism as body growth and somatic sexual development remains a source of great interest and wonder. The once widely held
opinion that macrogenitosomia praecox was specifically related to disease of the
pineal gland, notably to tumors arising from it, has been generally discredited.
Almost all neurologists and endocrinologists now agree that the hypothalamus,
more especially the tuber cinereum, regulates growth and sexual maturation
and that it is disease of this area alone that leads to neurogenic pubertas praecox.
It will be understood, of course, that cases associated with gonadal or adrenal
tumor are excluded. It is unnecessary to review here the evidence that has led to
the abandonment of the pineal gland and the adoption of the hypothalamus as
the critical site for premature sexual development and maturation of intracranial
origin in man. Recent expositions of the argument may be found in the papers of
Heuyer, Lhermitte, De Martel and Vogt (1), Horrax and Bailey (2), and Weinberger and Grant (3).
This report concerns the neuropathological findings encountered in a female
child, 7 years of age, who presented well marked macrogenitosomia praecox
beginning very early in life. The value of the observations lies in the fact that
the lesion of the hypothalamus which was present, was small and discretely localized, did not damage the hypothalamus proper, and was not complicated by
secondary effects upon other parts of the brain.
TRUE HAMARTOMA OF HYPOTHALAMUS
369
and axillary hair was sparse. The external genitalia were well developed; the vagina admitted one finger and had an adult type of mucosa. The uterus was estimated to be of adult
size. No masses were palpated in the adnexae and none in the abdomen. Intravenous pyelograms were normal, as were roentgenograms of the skull including the sellar region. X-ray
studies of the skeleton demonstrated a skeletal age of from 14 to 17 years in various parts.
Estrogen excretion was low (8 to 21 I. U.) , and there was no urinary excretion of pregnandiol.
The 17-ketosteroid excretion ranged from 3.9 mg. to 6.5 mg. Her intelligence quotient was
95 and she never exhibited premature psychosexual behavior.
Because of the suspicion of an ovarian tumor, laparotomy was performed on the child
when she was 7 years and 3 months of age. She died suddenly at the end of an otherwise
uneventful anesthesia.
Necropsy Findings
The general pathologic study (Dr. Benditt) showed that the uterus, Fallopian tubes,
vaginal epithelium and breast tissue were those of an adult, non-pregnant nulliparous woman. The ovaries contained many primordial follicles, one developing follicle and several
follicular cysts, but no corpora lutea. The adrenal, thyroid, parathyroid, and thymic
glands, and pancreas were normal. The pituitary gland weighed 0.54 Gm. and was microscopically normal.
Pathology of the Brain, Gross: At the base of the brain there was a nodular, egg-shaped,
pedunculated mass, the size of a navy bean (1 x 0.7 em.), which overlay and partly obscured
the mammillary bodies (fig. 1). This structure had the white color, the consistency and the
general appearance of nerve tissue; superficially it resembled the mammillary bodies themselves. It was covered completely by its own thin envelop of pia-arachnoid. Anteriorly it
was attached by a short filament to the posterior part of the tuber cinereum, just anterior
to the right mammillary body; posteriorly it was anchored to the anterior superior aspect of
the pons by a short, thick stalk. Thus it bridged across the interpeduncular and pontine
cisterns, as if slung in a hammock, and in no way pressed upon or distorted the hypothalamus or other parts of the base of the brain.
Downloaded from http://jnen.oxfordjournals.org/ by guest on October 29, 2016
FIG. 1. Sagittal section of brain showing the tumor-like hamartoma (H) lying between
the mammillary body and the pons. There is no compression or invasion of the normal appearing hypothalamus or third ventricle.
370
RICHARD B. RICHTER
Downloaded from http://jnen.oxfordjournals.org/ by guest on October 29, 2016
In all other respects the brain was entirely normal. There was not the least hydrocephalus, and there were no other malformations. The pineal gland was normal in size and in its
gross and microscopic appearance.
Microscopic Observations: The entire hypothalamus, together with the attached tumor
mass, was examined in complete serial sections, stained with cresyl violet and by the Niemer
technic for myelin. Sections of the abnormal formation were stained, in addition, with
hematoxylin-eosin, phosphotungstic acid-hematoxylin, and Van Gieson stains and by the
Holzer method for neuroglia fibers, the Perdrau method for reticulum, and the Bodian and
Davenport technics for nerve fibers.
The hypothalamus proper was anatomically intact and complete. All of the main nuclear
groups, the supra-optic, paraventricular, mammillo-infundibular, lateral and posterior
hypothalamic nuclei, the substantia grisea centralis and the mammillary bodies were fully
developed, were in their normal positions, and were alike on both sides of the brain. The only
possible exception to this were the nuclei tuberis which seemed somewhat underdeveloped
as regards those parts of the nuclei usually found lying medial to the optic tract. The main
nuclear masses, having the characteristic appearance of the tuberal nuclei, were located,
bilaterally, more lateral and dorsal than is usual. It seems probable that this represented
merely a normal anatomic variation. The neurons of the hypothalamic nuclei were, without
exception, well preserved and normal in appearance as well as in position. There was nothing
to suggest that there had been any local pressure upon them or degeneration from circulatory disturbances or other causes. The myelin fiber pattern was likewise normal throughout.
The tumor mass itself, in cresyl violet preparations, was clearly an essentially neural
structure throughout its entire extent. It was very cellular and was composed chiefly of
aggregations of normal, mature nerve cells (figs. 2a and 3a). They were separated into larger
and smaller groups and islands by bands of nerve fibers. While there was thus a somewhat
organized architecture to the structure, this was quite irregular, the arrangement of the
cell groups and fibers differing greatly from level to level. At the periphery of the mass
there was a circumferential zone, variable in width, which was relatively acellular, containing neuroglial nuclei but no neurons. The entire mass was invested by a delicate pia-arachnoid from which small blood vessels penetrated into its interior in the manner of normal
pial vessels.
The neurons, which composed the structure, were of various kinds. In general they all
bore a close resemblance to neurons encountered in one or another of the hypothalamic
nuclei, and could be divided into 5 main types (fig. 4). By far the most dominant cell form
was a small, round to oval, or occasionally more elongated neuron, possessing comparatively little cytoplasm and an easily visible nucleus with a distinct nuclear membrane (fig.
4a). The Nissl substance of such cells was finely granular or dust-like, when it stained at
all. These cells resembled those of the substantia grisea centralis of the hypothalamus and
in silver stains were almost all unipolor or bipolar. The majority of them were grouped
together in more or less discrete collections, but some were scattered in groups of nerve cells
of other types. Among the clusters of very small neurons were a few larger nerve cells, two
to four times as large, having a much more abundant cytoplasm which appeared either
homogeneous or contained some finely granular Nissl material concentrated in a rim at the
periphery of the cytoplasm (fig. 4b). Their nuclei were oval, sometimes indented, and were
usually displaced toward the periphery of the cell. The nuclei stained more darkly and were
less bistinctly defined than those of the smaller cells. Such neurons resembled ganglion
cells which are abundantly present in the posterior hypothalamic nuclei and sparsely seen
in the substantia grisea centralise A third distinct type of neuron, encountered in rather
extensive groups by themselves, was a large cell with abundant cytoplasm whose borders
were indistinct, having a nibbled or frayed appearance (fig. 4c). The numerous Nissl bodies
with which these cells were provided were irregular in size, shape and arrangement; the
largest and most heavily stained being collected in masses at the periphery of the cytoplasm in a discontinuous manner. Such cells were rounded or bluntly triangular and had
large, eccentric, vesicular nuclei with very distinct nucleoli and nuclear membranes. In all
TRUE HAMARTOMA OF HYPOTHALAMUS
371
respects these cells were like those of the nucleus mamillo-infundibularis of the hypothalamus. In most parts of the mass there were seen one or two small groups of cells having a still
different appearance. These neurons were small, multipolar, pyramidal or oval in shape,
Downloaded from http://jnen.oxfordjournals.org/ by guest on October 29, 2016
FIG. 2.
a. Representative field showing neuronal constituents of the hamartoma. Cresyl violet
stain.
b. Hypertrophic astrocytes within the hamartoma. Phosphotungstic acid hematoxylin
stain.
and had smooth discrete outlines (fig. 4d). Their nuclei were oval, centrally placed, and
often possessed one or more fine, linear folds in the nuclear membrane. Their moderately
plentiful cytoplasm contained well stained Nissl material, irregularly disturbed in dust-like
FIG. 3.
a. Hamartoma (H) attached by a neural stalk (8) to the lateral part of the tuber cinereum (T). Mammillary body (M). Third ventricle
(Viii). Cresyl violet stain.
b. The same stained for myelin by the Niemer method. Note the myelin fibers in the hamartoma, their concentration dorso-laterally, and the discrete myelinated fiber tract (TR) in the lateral part of the stalk.
c. Myelin stain of the hypothalamus showing the tract of myelinated fibers (TR) traversing the tuber cinereum after leaving the
stalk of the hamartoma. Fornix bundle (F).
Downloaded from http://jnen.oxfordjournals.org/ by guest on October 29, 2016
~
"1
;0
tz:j
8
~
(1
1-004
;0
~
t:l
::0
>
~
(1
1-004
;0
l\:J
TRUE HAMARTOMA OF HYPOTHALAMUS
373
or coarser granules. These cells were very like those of the nuclei tuberis. A fifth order of
neuron that was met in small numbers within the abnormal structure, were medium-sized
to large, fusiform or pyramidal cells whose most outstanding characteristic was their
similarity to the neurons of somatic motor nuclei (fig. 4e). Their Nissl substance was in the
form of large, usually rod-like fragments having a typical stichochrome arrangement. The
nuclei and nucleoli were large and there was no clear nuclear membrane. Cells of this class,
unlike the other varieties, did not occur in large and distinct fields of uniform neuronal
composition, but were found singly or in small groups of two to four cells, lying usually
near the periphery of the mass. Such neurons were not completely homologous with any
of those of the normal hypothalamus but most nearly resembled those of the nucleus intercalatus.
It was especially noteworthy that in van Gieson preparations no formations were seen,
either within the neurons of any type or in the intercellular tissue, that resembled or could
be interpreted as secretory granules.
In the cresyl violet preparations, neuroglial nuclei of all types were present in the tumorlike mass in the same numbers and proportions as they occur in the normal gray and white
matter of the central nervous system. In phosphotungstic acid-hematoxylin and Holtzer
preparations, however, it was apparent that there were large numbers of hypertrophic
fibrillary astrocytes, most numerous at the periphery, but present throughout the formation
(fig. 2b). There was corresponding fibrillary gliosis, densest at the periphery where heavy
bundles of tightly interlaced fibers formed a "vide, thick membrane limitans parietalis.
Toward the center of the mass the glia fiber network was looser but still definitely excessive. Only in respect of this gliosis did the tumor mass differ from normal brain tissue.
Downloaded from http://jnen.oxfordjournals.org/ by guest on October 29, 2016
FIG. 4. Drawings of neurons from the hamartoma illustrating the various types present.
All of them resemble neurons encountered in cell groups of the normal tuber cinereum, as
follows: (a) substantia grisea centralis (b) same (c) nuclei mammillo-infundibularis (d)
nuclei tuberis (e) nucleus intercalatus (?).
374
RICHARD B. RICHTER
DISCUSSION
While the lesion evidently responsible for the precocious puberty in this case
was a tumor mass, it was clearly not neoplastic, but represented a developmental
malformation. Such a misplaced structure would appear to be akin to the heterotopias; yet it cannot be regarded as a simple ectopia, as Dorothy Russell points
Downloaded from http://jnen.oxfordjournals.org/ by guest on October 29, 2016
There was no excess of collagenic connective tissue in van Gieson stains or of reticulum
fibers in the Perdr~u preparations.
The attachments of the tumor mass to the brain call for special comment. The posterior
strand, connecting its posterior extremity with the pons, was composed entirely of connective tissue, derived from the meninges. The anterior stalk, however, which joined it to the
hypothalamus was, like the formation itself, a neural structure, passing from the anterior
pole of the mass upward and forward to attach in the angle between the infero-medial part
of the circumference of the mamillary body, and the lateral extremity of the substantia
grisea centralis (fig. 3a). The stalk measured 1 mm. in breadth. Its medial half was composed
of gray matter, made up mostly of small neurons similar to those of the substantia grisea
centralis, with which were mingled cells like those pictured in Figure 4b. The lateral half of
the stalk was occupied by a round compact tract of nerve fibers surrounded by a ring or
crown of nerve cells with a structure like those of the nucleus mamillo-infundibularis.
In Niemer as well as in Bodian and Davenport preparations numerous nerve fibers,
many of them myelinated, were seen within the tumor formation. Some of them were arranged in a network of small fibers, while others were collected in small sweeping bundles,
curved or straight. Fibers of this kind 'were present at all levels of the mass, but showed no
constant pattern except at its rostral pole. Here there was a peripheral concentration of
myelinated fibers at the dorso-lateral part of the circumference of the tumor mass (fig. 3b).
This aggregate of fibers, as it was followed rostrally, was seen to migrate gradually to a
more dorsal and lateral position until it came to occupy the lateral part of the stalk itself,
where it assumed the form of a compact bundle of nerve fibers. In the silver preparations
it was particularly clear that a definite group of axis cylinders streamed from the dorsolateral part of the tumor formation toward and into the bundle of nerve fibers which made
up the lateral portion of the stalk attaching the mass to the hypothalamus. Immediately
rostral to the stalk this same bundle of fibers appeared as a compact tract 0.6 mm. in diameter, lying in the lateralmost part of the eminentia saccularis, just beneath the mammillary body. From here the tract could be followed rostrally in the tuber cinereum through
90 sections (fig. 3c). Throughout its course it lay 0.3 mm. ventral to the ventral border of the
mammillary bo.ly but did not enter or have fiber connections with that structure. At its
rostral extremity it maintained its same diameter and was located 1 mm. dorsal to the
ventral border of the tuber cinereum and 0.8 mm. lateral to the wall of the third ventricle.
Unfortunately, its rostral termination could not be determined with certainty, as it appeared to be lost in the gap between the two blocks into which the hypothalamus was
divided for sectioning. No certain extension of it could be identified in the caudalmost sections of the block rostral to it. The myelinated fibers of the tract, where it lay in the tuber
cinereum, were quite large and had the peculiar braided appearance characteristic of the
fornix bundles. It did not, however, join the fornix in that part of its course where it could
be followed. The same fiber tract was clearly seen in sections stained with cresyl violet and
in these it was demarcated by the same garland of nerve cells in its course through the
tuber cinereum that surrounded it in the stalk, although they decreased in number in a
rostral direction. No such formation, either fiber tract or associated neurons, was present
on the left side of the tuber cinereum. It appeared, then, that a definite fiber pathway
projected from the tumor-like appendage of the hypothalamus to an undetermined level
in the tuber cinereum. This connection is depicted in the projected drawings from the
serial sections shown in Figures 5 and 6.
375
TRUE HAMARTOMA OF HYPOTHALAMUS
out in her case, because adjacent parts of the brain were fully and normally developed. It is, therefore, classified as an hamartoma, using this term in the sense
of a tumor-like collection of normal tissue lodged in an abnormal location. Discrete heterotopias of considerable size are occasionally encountered within the
substance of the hypothalamus. I have had the opportunity to examine one
such ectopia from the collection of Dr. Paul Yakovlev. It occurred in the brain
of an infant, not known to have pubertas praecox, presenting a densely packed
aggregation of small mature neurons, along with a few larger ones, located on one
side of the hypothalamus in the region of the dorsomedial hypothalamic nucleus
eM
VIII
SEC110
SECI€O
H
H
CM
VIII'
CM
V III
SEC100
SEC92 •
T
FIG. 5. Projected drawings from serial sections stained by the Niemer method for myelin
and the Davenport method for axons, demonstrating the passage of nerve fibers from the
hamartoma (H) through its stalk to the tuber cinereum (T). Mammillary body-(OM).
Third ventricle-(Viii). Sections 160 to 92 are in a caudal to rostral series.
and the area hypothalamica posterior. It measured 4 mm. across at its largest
extent.
The great bulk of the pathological material pointing to the hypothalamus as
the determining location for the production of neurogenic pubertas praecox consists of tumors, mostly gliomas of various sorts, arising within or invading the
floor and walls of the third ventricle. Upward of twenty reports of this kind are
now on record. Many of them are of comparatively limited localizing value,
either because of the great size of the tumors involved, and the extensive damage
to structures in the hypothalamic area, or because of inadequate microscopic
Downloaded from http://jnen.oxfordjournals.org/ by guest on October 29, 2016
~1I1
eM
376
RICHARD B. RICHTER
examination of the region. A fe\v of the more completely studied cases, however,
permit better localization. Heuyer, Lhermitte, De Martel and Vogt (1) described
a comparatively small tumor, in which the dominant elements were ependyma-
Downloaded from http://jnen.oxfordjournals.org/ by guest on October 29, 2016
V lit
TC
6. Projected drawings of serial sections of the hypothalamus stained for myelin
showing the course of the fiber tract (TR) as it passes through the tuber cinereum (TC) after
leaving the stalk of the hamartoma. Mammillary body-(CM). Fornix-(F). Third ventricle
-(Viii). Sections 92 to 12 are in a caudal to rostral series.
FIG.
like cells (ependymo-glioma). The tumor invaded and distorted chiefly the tuber
cinereum and the mamillary bodies, more on the right side. De Lange (5) reported
an instance of a fibrillary astrocytoma (glioma durum) of the optic nerve which
TRUE HAMARTOMA OF HYPOTHALAMUS
377
Downloaded from http://jnen.oxfordjournals.org/ by guest on October 29, 2016
had infiltrated the hypothalamus in a rather restricted fashion, being limited
to the tuber cinereum, where it invaded and partly destroyed the ventro-median
nuclei (substantia grisea centralis) and, to a lesser degree, the nuclei tuberis
and mammillo-infundibularis. More recently Papez and Ecker (6) have given an
account of a rather large tumor composed of pituicytes (infundibuloma, as
such tumors were named by Globus (7)), attached to the tuber cinereum. Microscopically the damage to the hypothalamus was extensive, but selective. The
median eminence, ventro-medial nuclei and lateral tuberal nuclei were completely destroyed; the left mammillary body and posterior hypothalamic nucleus
showed much damage. The anterior hypothalamus and its nuclei, on the other
hand, were almost completely intact. A case of Dott's (8) showed fairly well
localized involvement of hypothalamic components. This was an astrocytoma
which was seen to infiltrate and destroy the mammillary bodies and the floor
of the third ventricle between them, and the posterior portion of the tuber
cinereum. From this group of cases of hypothalamic tumor, selected as most
suitable for purposes of localization, it seems clear that pubertas praecox may
and does result from damage to the posterior hypothalamus alone. Usually
both the tuber cinereum and the mammillary bodies are invaded; the former
with more regularity, perhaps, than the latter. When only these selected cases
are considered, one cannot agree with Weinberger and Grant (3), who take the
position that it is in the mammillary bodies that the neural component of the
sex mechanism is located. The tuber cinereum would appear to be of equal or,
possibly, even greater importance. It is of interest in this connection that the
pathological evidence is in accord with the experimental result of Bustamente
(9), who found in young rabbits that electrolytic lesions in the tuber cinereum
regularly led to obvious disturbances of sexual development, whereas those
restricted to the mammillary bodies did not.
The same intimate anatomical relationship to the tuber cinereum is encountered in those non-destructive hypothalamic lesions, the hamartomas. Of these,
there are now four indubitable specimens on record, including the present
example. The first was reported by Le Marquand and Russell (10) in a female
patient who had shown the first signs of precocious puberty at the age of 14
'months. The lesion was a tumor mass, 1.5 cm. in diameter, attached to the
right mammillary body and to the left side of the tuber cinereum. Microscopically, it was composed of collections of fully differentiated neurons separated
by a few bundles of myelinated fibers. It was noted that the zone of attachment
to the mammillary body was traversed by some of the myelinated fibers. A
few years later Driggs and Spatz (11) reported a similar formation in a male
who, at the age of 3 years, presented skeletal and sexual development of a boy
of 15. The lesion was a small discrete tumor mass, 1 em. in diameter, which
lay at the base of the brain and was attached to the posterior part of the tuber
cinereum in a sessile manner by a broad, short stalk or zone of apposition. The
mass was composed of many well differentiated neurons, likened by the writers
to those of the mother substance (the hypothalamus). Fine myelinated fibers
were present in the structure, but no passage of fibers was observed between the
378
RICHARD B. RICHTER
Downloaded from http://jnen.oxfordjournals.org/ by guest on October 29, 2016
tumor formation and the tuber at the site of its attachment there. More recently,
Bronstein, Luhan and Mavrelis (12) published the description of a similar case
in a female who showed signs of precocious puberty at a very young age, including vaginal bleeding at 22 months. Here again, the lesion was a small mass
at the base of the brain, in close relation to the tuber cinereum and attached to
it by a stalk. The principal elements, composing the mass, were small neurones
which were referred to as "immature." Myelinated nerve fibers were seen in
the structure, but no actual nerve fiber continuity could be demonstrated, via
its stalk, between the tumor mass and the hypothalamus.
In several important respects these four cases were similar, indeed almost
identical:
1. The striking and unmistakable signs of macrogenitosomia praecox associated with them appeared very early in life.
2. The lesions were small and well delimited and, in every case, the hypothalamus proper was anatomically normal.
3. All of the formations were composed primarily of well differentiated nerve
cells, resembling closely those of the normal hypothalamus. The predominant
type of cell was a small neuron similar to that of the substantia grisea centralis
(ventro-medial nucleus), a part of the hypothalamus stnading in close relation
to the pars nervosa of the hypophysis.
4. All contained nerve fibers.
5. Without exception there was anatomical continuity, usually by way of a
distinct stalk, between the abnormal mass and the tuber cinereum.
In the cases of Driggs and Spatz and of Le Marquand and Russell, the neuroglia in the malformation was normal or nearly so; in my case and that of Bronstein, Luhan and Mavrelis and glia was hyperplastic. This is probably not a
significant difference, but there is one very important distinction between the
cases. The examples of Driggs and Spatz and of Bronstein, Luhan and Mavrilis
possessed no nerve fiber connections between the tumor formation and the
brain or, more specifically, the hypothalamus, while in Le Marquand and
Russell's case there were indications of such connections. In the present case
particularly, a well defined fiber tract passed from the tumor mass into the
tuber cinereum or vice versa.
An element of confusion has been introduced into this matter of hypothalamic
hamartoma by virtue of the fact that some writers have indiscriminately classified tumors or other glial and connective tissue formations that show little
activity and neoplasia, as hamartomas. Thus Gross (13) calls a frankly invasive
glioma of his own series, together with the ganglioneuroma of Horrax and Bailey
and the ependymoma of Heuyer, hamartomas, and groups them with the cases
of the kind dealt with in this paper. Weinberger and Grant (3) do the same, and
in addition, add a large, fibrillary, acellular tumor of their own to the group.
It is true that certain glioblastomatous formations and connective tissue anomalies, that cannot be classified strictly as neoplasms, may occasionally be situated
in the hypothalamus and be accompanied by pubertas praecox. Krabbe's (14)
examples of tuberous sclerosis are a case in point and so too, probably, is a
TRUE HAMARTOMA OF HYPOTHALAMUS
379
Downloaded from http://jnen.oxfordjournals.org/ by guest on October 29, 2016
patient under my observation who has multiple signs of von Recklinghausen's
disease, macrogenitosomia praecox, and a suprasellar calcification. The unusual
lesion described by Meyer (22) in a 13-year-old girl with precocious puberty
and obesity is more difficult to classify. This large tumor, lying rostral to the
optic chiasm at the base of the brain, distorted the hypothalamus from which
it arose and replaced the right tuber cinereum. While the formation contained
nerve fibers and some nerve cells, there were other components as well such as
monster astrocytes, imperfectly formed tubes of ependymal cells and areas of
mucoid degeneration, all suggesting a developmental blastomatous process,
closely related to ganglioneuroma. Moreover those neurons present in the tumor
bore no resemblance to those of the hypothalamus. To call such anomalies, or
tumors, hamartomas is both erroneous and unfortunate, for the two are totally
different, not only in structure, but also presumably in functional activity.
Surely these strictly neural hamartomas, representing an accessory hypothalarnus,
as it were, are in a class a part.
In the case of destructive tumors it may be assumed that the stimulation of
sexual development depends either upon stimulation of the tuber cinereum during
a phase of the invasion by the tumor or upon release of the tuberal activity by
destruction of an inhibitory structure. The physiological implications of the
hamartomas are different. They represent redundant, excess, neural (hypothalamic) tissue, and it would appear that they produce their effects by their own
functional activity. That such is the case is indicated by the fact that the nerve
cells, composing the formations, always resemble those of the tuber cinereum
and that every known instance of hypothalamic hamartoma of this kind has
been associated with pubertas praecox. It is of interest, too, that none of the
hamartomas resemble the mammillary bodies in architecture or cellular composition. Their component neurons, in the main, bear a likeness to those of the tuber
cinereum; a further item of evidence that the tuber and not the mammillary
bodies controls growth and sexual development.
In what way the hamartoma influences sexual maturation is unclear, just
as the manner in which the normal hypothalamus regulates gonadotropic functions remains obscure. Every discussion of this normal mechanism raises the
issue of three theoretical possibilities:
1. A neural influence of the hypothalamus upon the gonadotropic activity
of the hypophysis.
2. Direct neural influence of the hypothalamus upon the gonads by way of
the spinal cord and autonomic pathways,
3. A direct neurosecretory function of the hypothalamus. The present material appears to furnish a suggestive clue on this point. Driggs and Spatz,
from the study of their specimen of hamartoma, stated the belief that the abnormal formation led to precocious puberty by a mere increase of neuro-hormonal activity on the part of the superfluous tuber cinereum tissue. The lack
of demonstrable nerve fiber connections between the hamartoma and other
structures seemed to be the principal reason for concluding that the activity in
their case was neurosecretory, In my case, on the contrary, the distinct nerve
380
RICHARD B. RICHTER
SUMMARY
An ectopic malformation of the hypothalamus, associated with pubertas
praecox in a young female child, is described. The lesion is classified as an hamartoma in the sense of a tumor-like collection of normal tissue lodged in an ab-
Downloaded from http://jnen.oxfordjournals.org/ by guest on October 29, 2016
fiber pathway between the hamartoma and the tuber cinereum strongly favors
a neural mechanism. It must be said that the exact termination of the fiber
tract in the hypothalamus was not established and that it is not known whether
it was efferent or afferent with respect to the hamartoma. The twisted arrangement of the fibers in the tract and the garland of neurons that surrounded it,
lead one to consider the possibility that it is an aberrant bundle of the fornix,
making connection with the hamartoma. Whether this be the case or not, the
very existence of so definitive a nerve fiber connection between hamartoma and
tuber cinereum is highly indicative of neural rather than humoral action. It
may be said, also, that the absence within the hamartoma of secretory granules,
such as have been described in the hypothalamus of man by Gaupp and Scharrer
(15), Roussy and Mosinger (16), and by Scharrer and Scharrer (17) speaks to a
certain extent against neurosecretory activity of the structure.
Hypothalamic hamartomas, representing as they do, redundant or accessory
tuberal substance, may be thought to lead to the development of pubertas
praecox either through sheer excess of neural activity or because, unlike the
tuberal center themselves, they lack some other neural inhibitory control. The
prevailing opinion appears to be that the tuber cinereum regulates sexual maturation by way of its neural control of the gonadotropic activity of the adenohypophysis. If this be so, the problem as to how the tuber cinereum (or in this
case the hamartoma) plays upon the gonadotropic activity of the pars distalis,
whether by direct secretory nerve fibers to it, or by an intermediate humoral
link through the neurohypophysis as suggested by Harris (18), Green (19) and
others, is outside the scope of this discussion; nor do the observations on this
case add anything to its solution.
In the light of recent work, by Kriicke and by Nowakowski it appears that
more consideration should be given to the possibility that hypothalamic centers
may exert vegetative control on the gonads via a direct descending diencephalicspinal sympathetic pathway. Kriicke (20) describes in man a tract of unmyelinated and lightly myelinated fibers, running the entire length of the spinal
cord in the central gray matter. This he believes to be a continuation of the
medial part of a similar collection of fibers, the fasciculus periependymalis,
which arises from nuclei of the posterior hypothalamus and traverses the brain
stem, lying in the central gray matter of the floor of the fourth ventricle. He
regards it as an efferent sympathetic pathway from the hypothalamus to spinal
centers. Physiological support is given to this conception by the experiments of
N owakowski (21), who reports that ovulation which, as is well known, can be
induced in female rabbits in heat by electrical stimulation of the tuber cinereum,
is prevented by complete section of the spinal cord at levels between T-12 and
L-2.
TRUE HAMARTOMA OF HYPOTHALAMUS
381
normal location. The formation was found to be a neural structure and represented essentially an excess of tuber cinereum tissue. The case is discussed in
relation to 3 similar ones reported in the literature. Because the structure contained nerve fibers and was connected with the tuber cinereum by a discrete
bundle of myelinated fibers, it is suggested that it produced its endocrine effect
through a neural influence, direct or indirect, either upon the adenohypophysis
or more directly upon the gonads via a spinal sympathetic pathway.
DISCUSSION
Downloaded from http://jnen.oxfordjournals.org/ by guest on October 29, 2016
Prof. W. Scholz, Munich, Germany: Every case of these tumor-like malformations seems to present the same picture. We had the opportunity to investigate
a very similar case. Besides the structures which were just described, we had,
too, some ependymal formations within the tumor. I don't know whether in
Dr. Richter's case products of secretion of nerve cells could be observed.
The case we had at our institute had large nerve cells in the malformation
which apparently contained two or more vacuoles filled with peculiar colloidal
droplets, a nerve cell activity described by Scharrer and Gaupp as "Neurocrinie."
It might be that a higher degree of such a secretion is of some significance in the
causation of pubertas praecox.
The precocious development in our case was significant not only in relation
to the sexual features, but also because this girl, a little over eight years of age,
manifested definite arteriosclerotic changes: the basilar artery exhibiting characteristic, highly hypertrophic changes in the intima.
I would like to ask whether special attention was paid by Dr. Richter to the
process of "Neurocrinie" and to the larger arteries at the base of the brain.
Dr. Richter, Chicago, Ill.: First I might answer that there were no changes in
the large arteries of the brain or in those elsewhere in the body.
Dr. Scholz's comments raise some interesting and important points. The
admixture of ependymal cells in the lesion examined by him brings up the question of what an hamartoma really is. In the title of this paper I have designated
the lesion as a true hamartoma because it seemed to me that a great deal of
confusion has arisen from classifying neoplastic lesions, that do not show very
much neoplastic activity as hamartomas. For example, Gross, when reviewing
a series of cases of pubertas praecox associated with hypothalamic lesions,
included an ependymal glioma of Henyer, L'Hermitte and de Martel, a ganglioneuroma of Horrax and Bailey, together with a frankly infiltrating glioma of his
own, as hamartomas. Weinberger and Grant followed suit and added a somewhat
inactive fibrillary neoplasm to this group, calling them all hamartomas.
Certainly the physiological implications of neoplasms which are destructive
for the hypothalamus and of these lesions which do not damage the hypothalamus, but appear actually to add mature hypothalamic tissue, must be quite
different. This lesion, I think, acts as a functioning unit to induce pubertas
praecox. How it does so is another matter. It may be through sheer exuberance
of neural activity or possibly the hamartoma, which unlike the physiological
tuber mechanism, is not under the control of some inhibitory center or structure.
382
RICHARD B. HICHTER
As I have already said, the presence of a distinct fiber tract between the hamartoma and the tuber cinereum in this case suggests that the influence exerted by
the lesion is a neural one. Furthermore, van Gieson preparations of the hypothalamus and of the hamartoma failed to demonstrate any structures in the
nerve cells of either that could be interpreted as secretory granules similar to
those described by Scharrer and Gaupp, and by Roussy and Mosinger. But the
problem, as to whether the tuber cinereum (and hamartomas of it) exert their
effects upon sexual development by direct neurosecretory activity, or via the
hypophysis, whether by direct innervation of the pars distalis or through some
humoral link to it, or by a more direct sympathetic pathway to the gonads by
way of the spinal cord, must, for the present, be left open.
1. HEUYER, G., LHERMITTE, J., DE MARTEL, AND VOGT, C.: Un Cas de Macrogenitosomia
Precoce Liee a un Ependymogliome de la Region Mamillo-tuberale. Rev. neurol.,
T. 2: 194, 1931.
2. HORRAX, J., AND BAILEY, P.: Pineal Pathology. Arch. Neurol. & Psychiat., 19: 394,
1928.
3. WEINBERGER, L. lVI., AND GRANT, F.: Precocious Puberty and Tumors of the Hypothalamus. Arch. Int. Med., 67: 762,1941.
4. SECKEL, H. P. G., SCOTT, W. W., AND BENDITT, E. P.: Six Examples of Precocious
Sexual Development. I. Studies in Diagnosis and Pathogenesis. Am. J. Dis.
Child., 78: 484, 1949.
5. DE LANGE, C.: Zur Klinik und pathologischen Anatomie der hypothalamischen Form
von Pubertas praecox. Ann. paediat., 161: 113, 1943.
6. PAPEZ, J. W., AND ECKER, A.: Precocious Puberty with Hypothalamic Tumor (Infundibuloma). J. Neuropath. & Exper. Neurol., 6: 15, 1947.
7. GLOBUS, J. H., AND R. S.: Infundibuloma. A Newly Recognized Tumor of Neurohypophysial Derivation wi th a Note on the Saccus Vasculosus. J . Neuropath. & Exper.
Neurol., 1: 59, 1942.
8. DOTT, N. M.: Surgical Aspects of the Hypothalamus. In CLARK, W. E. L., BEATTIE,
J., RIDDOCH, G., AND DOTT, N. M. The Hypothalamus: Morphological, Functional, Clinical and Surgical Aspects. London, Oliver and Boyd, 1938.
9. BUSTAMENTE, M.: Experimentelle Untersuchungen uber die Leistungen des Hypothalamus, besonders bez uglich der Geschlechtsreifung. Arch. f. Psychiat., 115:
419, 1942.
10. LE MARQUAND, H. S., AND RUSSELL, D. S.: A Case of Pubertas Praecox (Macrogenitosomia Praecox) in a Boy Associated with a Tumor in the Floor of the Third
Ventricle. Roy. Berkshire Hosp. Rep., 1934-35, p. 31.
11. DRIGGS, M., AND SPATZ, H.: Pubertas praecox bei einer hyperplastischen Missbildung
des Tuber cinereum. Virchows Arch., 305: 567, 1939.
12. BRONSTEIN, I. P., LUHAN, J. A., AND MAVRELIS, W. B.: Sexual Precocity Associated
with Hyperplastic Abnormality of the Tuber Cinereum. Am. J. Dis. Child., 64:
211, 1942.
13. GROSS, R. E.: Neoplasms Producing Endocrine Disturbances in Childhood. Am. J.
Dis. Child., 59: 579,1940.
14. KRABBE, K.: La Sclerose Tubereuse du Cerveau (Maladie de Bourneville) et I'Hydrocephalie dans leur Relations avec la Puberte Precocc. L'Encephal. 17: 281,1922.
15. GAUPP, R., AND SCHARRER, E.: Die Zwischenhirnsekretion bei Mensch und Tier.
Ztschr. f. d. ges. Neurol. u. Psychiat., 153: 327,1935.
Downloaded from http://jnen.oxfordjournals.org/ by guest on October 29, 2016
REFERENCES
TRUE HAMARTOMA OF HYPOTHALAMUS
383
Downloaded from http://jnen.oxfordjournals.org/ by guest on October 29, 2016
16. Rotrss r , G., AND MOSINGER, M.: Processus de Secretion Neuronale dans les Noyaux
Vegetatifs de I 'Hypothalamus chez I 'Homme, la "Neuricrinie." C. R. Soc. de
BioI. Paris, 115: 1143, 1934.
17. SCHARRER, E., AND SCHARRER, B.: Secretory Cells within the Hypothalamus. Res.
Pub. Assn. Nerv. & Ment. Dis., 20: 170,1940.
18. HAeRIs, G. W.: Electrical Stimulation of the Hypothalamus and the Mechanism of
Neural Control of the Hypophysis. J. PhysioI. 107: 418, 1948.
19. GREEN, J. D.: The Histology of the Hypophysial Stalk and the Median Eminence in
Man with Special Reference to Blood Vessels, Nerve Fibers and a Peculiar N eurovascular Zone in this Region. Anat. Rec., 100: 273, 1948.
20. KRUCKE, W.: tiber das Langsbundel in der Substantia gelatinosa centralis des Riickenmarks (Fasciculus parependymalis) und iiber seine Bedeutung fur die Verbindung der vegetativen Zentren des Hirnstammes mit denen des Riickenmarks.
Deutsche. Ztschr. f. Nervenheilk., 160: 196, 1949.
21. NOWAKOWSKI, H.: Zur Auslosung der Ovulation durch elekrische Reizung des Hypothalamus und ihre Beeinflussung durch Riickenmarkdurchschneidung. Acta
N eurovegetativa, 1: 13: 1950.
22. MEYER, J. E.: Pubertas praecox bei einer hyperplastischen Missbildung des Hypothalamus. Arch. f. Psychiat., 119: 378, 1948.