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Original
Article About Dexters
"The
Significance of an Achondroplasia-Like Condition Met With in Cattle"
Part VI
by F.A.E. Crew
in Proceedings of the Royal Society of London,
volume 95, 1923, pages 228-255.
Page 241
VI - The Etiology of Achondroplasia
In the case of the human many and varied causes have been suggested: Bohn
and Schwob as early as 1868 suspected a disturbance or an insufficiency of
the placenta. Parrot (1876) considered that a congenital nutritive
disturbance of the cartilage cells was responsible. Klebs (1889) suggested
that a compression of the foetus by the umbilical vesicle was the cause. Von
Franqué (1893) and Rindfleisch (1889) also suspected mechanical pressure.
Dor (1893) that an autointoxication was the cause. Poncet and Leriche
considered that the achondroplasts constituted a distinct race, while Buck
and Mayer (1900) held that the condition was a hereditary process and that
the most severe cases were the last of a degenerate race. Porak and Durante
(1905) inclined to the opinion that the condition was sclerosis of cartilage
resulting from an autointoxication. Cestan and Regnault described the
condition as a form of intrauterine rickets. Marie (1900) suspected
abnormality of some gland of internal secretion, while Lugano and Devay
agreed with Leblanc in regarding a malfunctioning of the thyroid as the
cause. Collman described a case in which the thyroid was much enlarged, as
did also Virchow and Neumann. Bowlby, on the other hand, records a case in
which the thyroid was absent. Regnault, however, concludes that in the
majority of cases this gland is normal. Vargas held that the thymus was
responsible, while Parhon, Shunda and Zalplachta (1905) went further by
suggesting that the condition was due to a combination of hypofunctioning of
the pituitary, thyroid, and thymus, together with a hyperfunctioning of the
sexual glands. Murk Jansen advanced an ingenious hypothesis to explain the
conditions found in these cases. He argues that the responsible cause is a
compression of the foetus by a too small amnion or by a hydramnios. Keith
disagrees emphatically with Jansen’s conclusions, pointing out that a
comparison of such contrasted conditions as the fronto-cephaly of
achondroplasia and opisthocephaly and simoproposia leads directly to the
conclusion that such differences in end-results can be explained in terms of
different action on the part of the agencies regulating growth. This
growth-regulating mechanism is in all probability the endocrine system, and
Keith argues that in the light of recent advances in endocrinology it is
indeed probable that the stimulus which brings about the preparatory
pre-ossification changes in bone formation is an internal secretion “such as
we may expect to arise either in the pituitary, thyroid, suprarenal or
genital glands, or by an interaction of secretions from all of these,” and
that the cause of achondroplasia is a malfunctioning of one or more of these
glands of internal secretion.
Page 242
The present study has not furnished a complete answer as to which, if any,
of the glands of internal secretion is to be regarded as the responsible
causal agent in the production of achondroplasia, granting, that is, that
this condition in the “bull-dog” calf is achondroplasia. But this much is
certain, there is profound abnormality in some of the ductless glands. If it
is desired to investigate the cause of achondroplasia in the human, the most
satisfactory way will be to maintain a herd of Dexters and to produce
abortion of fetuses during the first three months of pregnancy.
The Pituitary - In the case of the human achondroplast smallness of
the pituitary has been commonly reported, and this fact has been deemed to
be of some significance as it has been conclusively established that this
gland is concerned in the normal growth processes. But no definite and
constant histological abnormality of the pituitary has been found.
In the case of the “bull-dog” foetus the pituitary is definitely smaller and
is more compressed than in the normal. Histologically, it presents the usual
structure, save that in many cases there are areas of oxyphil cells in the
pars intermedia. The cells of the anterior lobe appear to be more
closely packed than is usual and the vascularity of the gland to be less
than in the normal. It is not profitable to discuss the possible
significance of such vague impressions as these. But advantage was taken of
the melanophore test devised by Hogben and Winton in order to examine the
functioning of the posterior lobe of the pituitary of the monstrous calf.
These workers have shown that following an injection of a minute quantity of
posterior lobe extract into a frog previously kept under those conditions
which conduce to skin-pallor, there is a very characteristic and rapid
darkening due to a marked expansion of the melanophores. In the case of the
normal cattle foetus the pituitary is active, as estimated by this test, at
the beginning of the third month. The pituitary is ground up in a mortar
with sand and distilled water and the extract injected intra-abdominally. In
the case of the “bull-dog” foetus, the pituitary of a six months’ specimen
gives a very doubtful reaction. A four months’ pituitary gives a still more
doubtful reaction. It is granted that this test is one for posterior lobe
activity and that a malfunctioning of the pituitary which would constitute a
possible cause of achondroplasia would be one involving the anterior lobe.
Nevertheless it would appear not to be without significance that in the
“bull-dog” foetus the posterior lobe is physiologically relatively inactive
at the fourth and the sixth months; it is not unreasonable to think that the
measure of the activity of the posterior lobe can be regarded as an
indication of the functioning of the gland as a whole.
Page 243
If this be so, then indeed there is reason to suspect that a malfunctioning
of the pituitary during the earlier months of foetal life is responsible for
the abnormalities in ossification and in growth. If, for example, the
pituitary does not function properly at the time when the normal processes
of ossification begin, and if, for the normal development of bone, the
guiding stimulus of the pituitary is necessary, then a retardation of
pituitary activity or an insufficiency of its secretion could lead to
abnormality in bone formation, and the degree of imperfection in the
end-results will vary with the degree of retardation of the pituitary
functioning and with the difference in the time at which the different parts
of the skeleton become ossified.
The suspicion that a malfunctioning of the pituitary may be involved in the
causation of the conditions found in the monstrous calf is strengthened by
the work of Krogh, who has shown that there is good reason to believe that
posterior pituitary substance is concerned in the production and maintenance
of capillary contractile tonus. Insufficiency results in capillary
dilatation and oedema. Pituitary malfunctioning in this way can lead to
anasarca, hydrocephalus and hydramnios. Moreover, it was found by Smith, and
this has been confirmed by Hogben, that general oedema commonly followed
injection of pituitary extract into larval Amphibians.
The Thyroid - In the case of the “bull-dog” foetus Seligmann (1904)
found that the thyroid was abnormal and concluded that the condition was one
of foetal cretinism. In seven cases the thyroid was oedematous and purple;
the isthmus absent or irregular in shape. Histologically, the gland
consisted of masses of more or less cubical or spheroidal cells and the
capillary network was extremely dense. Very few vesicles and sometimes only
the faintest trace of a vesicular arrangement could be detected. There was
complete or almost complete absence of colloid and the lumina of the
vesicles were packed with cells. In 1911, Sheather described the thyroid as
being normal in size, shape and histological structure, save that there was
a slight excess of interstitial tissue in some parts of the gland. The
vesicles were perfectly formed and filled with colloid. Crew and Glass
(1922) described the thyroids of five foetuses and demonstrated that in
these cases the thyroid did not show the histological features of a
hypo-functioning but rather of a hyper-functioning gland. In the large
series of cases which have now been examined the thyroid has varied
considerably. In some, mostly the younger specimens, it has been
unremarkable; in others it has been enlarged and the histological picture
has been that of a thyroid from a case of hyperthyroidism, no colloid being
present, the small irregular vesicles containing papillary ingrowths of
epithelium and desquamated
Page 244
material, and the section consisted of masses of solid cellular hyperplasia.
In the older specimens the thyroid showed the typical signs of involution,
the vesicles were enlarged, irregular and full of colloid, the epithelium
low and the previously hyperplastic intervening tissue undergoing
retrogression and transformation into fibrous tissue.
The sequence of events as suggested by the different histological
appearances seen in different cases would seem to be, first, a developing
thyroid, then a hyperplastic hyper-functioning thyroid, and finally an
involuting gland with fibrous atrophy and progressive hypo-functioning. Such
a scheme would accommodate the different descriptions which have been given
by previous writers and would explain the diagnosis of foetal cretinism.
This seriation of events is typical of cretinism, but it is also the typical
course of events which follows removal of the anterior lobe of the pituitary
in mammals, as has been shown by Cushing and more recently by Dott. The
lesions found in the thyroid do not necessarily indicate that the condition
is that of foetal cretinism. The mother of a monstrous calf is not goitrous
herself. Shattock, in Seligmann’s paper, suggests that the maternal thyroid
is probably sufficient for the mother’s needs only, but the experiments of
Halstead and of Edmunds on the dog show that were this so the thyroid of the
foetus would be greatly enlarged. The conditions found in the thyroid of the
“bull-dog” foetus can be regarded as secondary to a malfunctioning of the
pituitary.
Since Gudernatsch demonstrated the efficiency of thyroid feeding to
accelerate Anuran metamorphosis, the value and specificity of this test, at
least as an indicator of the iodine content of the gland, as demonstrated by
Lenhart and Swingle, has been universally recognised. Using the axolotl, the
larval form of the Mexican salamander, there is the opportunity of
demonstrating thyroid activity in a most spectacular way, for a single meal
of fresh gland suffices to induce metamorphosis. This is a critical test for
thyroid iodine, the transformation does not occur in aquaria without this
stimulus and it cannot be induced by the oral administration of inorganic
iodine. This axolotl test has been shown to be a specific test for thyroid
activity by Laufberger, Jensen, Kaufmann (L.), and Huxley and Hogben.
An axolotl weighing 64 grams was fed with 2 grams of fresh thyroid taken
from a seven months’ “bull-dog” foetus. Complete metamorphosis resulted,
with shedding of the larval skin in the usual 12 to 14 days after the
thyroid meal. A second axolotl of 23 grams was fed with 1 gram of thyroid
from a four to five months’ “bull-dog” foetus. Metamorphosis occurred with
shedding of the larval skin at about the same time as in the previous
instance. This
Page 245
test cannot be applied successfully before the fourth month of intrauterine
life in the case of the normal cattle foetus. From the fourth month onwards
the thyroid is active as estimated by this test, before this it is not. It
will be noted that according to the tests used, the pituitary is functional
before the thyroid.
These observations give a clear demonstration that there is present
physiologically active iodine in the thyroid of the monstrous calf of the
Dexter at an early stage of foetal life. They do not support the contention
that the condition is that of cretinism.
The Adrenals - In no case have these been perfectly normal. In some
there has been an undue amount of fibrous tissue in the cortex and in the
medulla. In the majority there have been areas of cartilage and in many
there are areas of cartilage bone with Haversian canals and areas of
calcified cartilage with osteoblastic bone on its surface. The different
stages in this bone formation would appear to be, hyperplasia of fibrous
tissue, formation of hyaline cartilage in these areas, fibrillation of the
cartilage, calcification in the matrix, absorption of the calcified
cartilage by osteoclasts, and deposition of osteoblastic bone on the
surface. The exact significance of this cartilage bone formation in abnormal
situations has not been established, but since similar areas have been found
in other organs in which there is plentiful connective tissue, it is
suggested that the condition is a general one and possibly is secondary to a
malfunctioning of the thyroid. In the cat, Blair Bell found areas of
calcification in the adrenal after thyroidectomy.
No other abnormality of the endocrine system was encountered. It may be
remarked, however, that in contradistinction to the general finding of
sexual precocity in the living human achondroplast, the differentiation of
the sex-organisation in the case of the monstrous calf of the Dexter is not
so advanced as in a normal cattle foetus of the same age.
The tentative conclusions arrived at from this study are as follows: Very
possibly the condition results from a malfunctioning of the pituitary
between the second and third month of intrauterine life. Under these
conditions the proper control of cartilage bone formation is lacking. The
thyroid undergoes hyperplasia, and this is followed by involution.
But it is not claimed that a definite answer has been given to the question
as to the primary cause of the condition. It is felt, however, that the
study of the monstrous calf of the Dexter has provided a strong argument in
favour of using this material for a complete and thorough study of the
conditions akin to achondroplasia. A small herd of Dexters would provide the
finest
Page 246
experimental material for a demonstration of the bearings of Genetics, upon
pathology and upon the science of animal breeding.
On to Part VII
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