ORAL' MANIFESTATIONS IN SYSTEMIC DISEASES ...

ORAL' MANIFESTATIONS IN SYSTEMIC DISEASES:
HYPOVITAMINOSES AND BLOOD DYSCRASIAS
Charles Tomes Lecture delivered at the Royal College of Surgeons of England
on
6th July, 1951
by
H. H. Stones, M.D., M.D.S., F.D.S.R.C.S.,
Professor of Dental Surgery, University of Liverpool.
THERE IS A wide diversity in the oral manifestations of systemic diseases,
and these depend both on the particular condition and sometimes on
the age of onset. Thus in the hereditary disease osteogenesis imperfecta,
the structure of the dentine may be affected, in which case the teeth vary
in colour from yellow to bluish-black. Severe metabolic disturbances
affect the developing and calcifying teeth. In icterus gravis, which is
associated with the Rh factor, the deciduous teeth may be pigmented
bluish-green. After several years the colour gradually becomes yellowishbrown.
As the jaundice usually improves before calcification starts in
the permanent dentition they are not usually involved. In various
osteodystrophies such as generalized osteitis fibrosa, the jaw bones may
be affected. Again, in certain diseases of the nervous system, there may
be paralysis of the muscles of the palate and tongue or other muscles,
or in others there may be neuralgia.
Many systemic diseases have an effect on the oral mucosa.
The following list (Stones, 1951) gives a classification of stomatitis and
other non-neoplastic lesions of the oral mucosa on an aetiological basis,
and it can be seen that the majority of them are associated with
disturbances affecting other parts of the body.
A. Traumatic, thermal, chemical, galvanic, actinic and irradiation
lesions.
B. Catarrhal stomatitis.
C. Stomatitis due to hypovitaminoses.
D. Stomatitis in the blood dyscrasias.
E. Stomatitis associated with specific micro-organisms or larvae.
F. Stomatitis associated with virus diseases.
G. Stomatitis associated with allergic conditions.
H. Stomatitis due to ingestion of metals and drugs.
I. Other miscellaneous diseases chiefly of obscure origin with oral
manifestations.
Thus the oral manifestations in systemic disease present an extensive
and fascinating study, and of these it is proposed to discuss the effect of
the hypovitaminoses and the blood dyscrasias. Though observations
will be chiefly directed to the oral changes, and these are important as
they sometimes exhibit the first signs of a serious disease, it must be
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ORAL MANIFESTATIONS IN SYSTEMIC DISEASES
emphasized that this is only one part of the organism and that a general
examination and, frequently, laboratory investigations are necessary,
before arriving at a diagnosis.
THE ORAL MANIFESTATIONS OF HYPOVITAMINOSES
The chief vitamins concerned with the subject are the vitamin B
complex and vitamin C. Deficiency of vitamins K and P are mentioned
when considering purpura.
Vitamin B Complex Deficiency
A deficiency of some components of the vitamin B complex is known
to have a marked effect on the oral tissues and this has been shown both
from observations in man and animal feeding experiments. The effect
of other components has not yet been worked out. There are often the
clinical features of multiple deficiencies.
The usual cause is a marked deficiency in the diet but the other factor
is the capacity of the organism to maintain the vitamin in a stable form,
and to assimilate it.
Aneurin or thiamnin deficiency.-It has been known for some years that
deficiency of this vitamin produces peripheral multiple neuritis as occurs
in beri-beri. It is doubtful if there are any definite oral lesions, though
Weisberger (1941) reported pinpoint herpetic-like vesicles occurring on
the palate and undersurface of the tongue that were cured by the
administration of aneurin. Mann, Spies and Springer (1941) state that
it may cause hyperaesthesia of the oral mucosa.
Riboflavin deficiency.-This produces characteristic oral lesions. They
have been described by Sebrell and Butler (1939) in their riboflavin
deficiency experiments on eighteen otherwise healthy women, and by
various observers including Sydenstricker (1941), Jones et al. (1944),
and by Braun, Bromberg and Brzezinski (1945) in their report on
pregnant women in Jerusalem. An interesting contribution has recently
been made by Welbourn, Hughes and Wells (1951) who have noted that
following subtotal gastrectomy about 10 per cent. of cases develop the
characteristic features of aneurin and riboflavin deficiency, either singly
or combined. The most frequent is a hyporiboflavinosis, though without
the desquamation of the nasolabial folds and ocular lesions. As both
aneurin and riboflavin are only stable in acid solution it may be that with
the achlorhydria following subtotal gastrectomy, a proportion of both is
destroyed. They point out that Melnick, Robinson and Field (1941)
have shown that up to 50 per cent. of thiamin may be destroyed by
incubation with bile or pancreatic juice at a pH of 8-0 to 8 5, though
the question of the stability of riboflavin has not been worked out in the
same detail.
In ariboflavinosis there is cheilosis in which the lips become red and
cracked. A characteristic feature is the development of red painful
areas at the angles of the mouth which in severe cases lead to the
formation of several fissures resembling perleche. An important
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H. H. STONES
predisposing factor is loss of the vertical dimension of the bite and
consequent sagging of the tissues as occurs in elderly edentulous patients.
Hence it is necessary to correct this loss (Ellenberg and Pollack, 1942;
Mann, Mann and Spies, 1945; Mann, Dreizen and Spies, 1948).
A painful glossitis is a feature in which there is sometimes engorgement
of the fungiform papillae, the denuded summits of which permit the
underlying capillary loops to appear as red elevations. It may be a
magenta colour. Later there is atrophy of the papillae so that the
tongue appears glazed, shiny and fissured.
Other rarer features that have been reported are inflammation of the
eyelids, conjunctivitis, disturbances of vision, and desquamation of the
epithelium of the nasolabial folds, alae nasi, eyelids and ears.
Nicotinic acid deficiency.-Pellagra is the chief disease associated with
a deficiency and in this Spies, Bean and Asche (1939) point out that
there is a multiple deficiency of the vitamin B complex including that of
riboflavin and aneurin. Secondary pellagra, in which there is failure to
assimilate the vitamin, has been described as occurring in association
with chronic intestinal disturbances such as peptic ulcer, carcinoma of
the stomach and ulcerative colitis (Bean, Spies and Blankenhorn, 1944).
In the early stages the tip and margins of the tongue become red.
This intensifies and the tongue becomes swollen and has a burning
sensation. As the condition progresses the lingual papillae atrophy
and there is desquamation of the superficial epithelial layers leaving a
red, smooth and glazed surface (Kruse, 1942). Gingivitis or stomatitis
which may be associated with fusospirochaetal organisms may develop,
the inflammation starting at the interdental papillae and progressing
until the gingivae are ulcerated. There is inflammatory involvement of
other mucous membranes of the alimentary tract and sometimes of the
perineum and vulva.
Other features include dermatitis with the formation of small
erythematous patches that eventually turn brown and desquamate. There
may be mental symptoms of varying severity.
The pellagrin often complains of tingling and numbness of the
extremities which are characteristics of beri-beri which may co-exist with
the disease.
The administration of nicotinic acid produces a striking improvement
in the inflammation of the mucous membranes, skin lesions and mental
symptoms. It does not, however, cure the angular lesions of the mouth
which arise from riboflavin deficiency, or the peripheral neuritis which is
due to aneurin deficiency.
Pyridoxine deficiency.-There is obscurity regarding the effects of
pyridoxine deficiency in man and no definite conclusions have been
reached. With the introduction of one of the antimentabolites desoxypyridoxine,
limited tests have been carried out on its effect. Mueller
and Vilter (1950) report eight cases who received 60 mgs. or 150 mgs. of
desoxypyridoxine daily. The other components of the B complex were
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ORAL MANIFESTATIONS IN SYSTEMIC DISEASES
at a low level but within normal range. After two to three weeks, oral
lesions developed similar to a combined riboflavin and nicotinic acid
deficiency. These remained unchanged when the latter vitamins, together
with aneurin, were given, but they disappeared within 48-72 hours after
pyridoxine was administered.
Pantothenic acid deficiency.-The effect of a deficiency of pantothenic
acid has not been elucidated in man, and the few reports in the literature
are based on the therapeutic test. Field, Green and Wilkinson (1945)
report six cases with glossitis and cheilosis at the angles of the mouth,
which were relieved by calcium pantothenate after failure of other
fractions of the vitamin B complex. The glossitis of these patients was
characterized by atrophy of all the papillae, absence of coat, and by
redness which was usually slightly purplish and darker than the scarlet
red of nicotinic acid deficiency.
Vitamin C Deficiency
Scurvy, which results from extreme depletion of vitamin C, is now
comparatively rarely seen in Great Britain. In four cases out of those
that have been personally observed the gingival condition has led to a
diagnosis of the deficiency. It typically occurs in middle aged or elderly
bachelors who neglect their diet.
There are marked oral lesions. The gingivae become swollen, maroon
coloured and spongy, tending to cover the teeth. Haemorrhages
frequently occur and the gingivae slough. Ecchymoses may also occur
on the palate and inner aspect of the cheeks. The lips and skin may
appear pale due to secondary anaemia. There is a tendency to bleeding
from other sites; thus subperiosteal haemorrhages occur in the long
bones so that bruising, particularly on the inner aspect of the knees and
near the ankle, is frequently observed. Effusion of blood into joints
causes haemarthroses.
Infantile scurvy.-Barlow's disease is seen in infants during the first
year, occurring in those who are bottle fed. Sometimes the first sign is a
purplish swelling of the gingivae round several teeth; this has recently been
observed in an infant, in whom a diagnosis of scurvy was.made from the
gingival appearance. The limbs are tender due to subperiosteal
haemorrhages, and the legs are characteristically flexed and everted;
ossification is distorted, and the lesions are usually bilateral.
It is doubtful, however, if a comparatively low intake has any marked
effect on the incidence of gingivitis. Undoubtedly during the world
wars in the winter months in Great Britain, there was a deficiency of
ascorbic acid in the diet. In an investigation carried out by Stones,
Lawton, Bransby and Hartley (1949) in an institutional school during
the second world war, the vitamin C intake was estimated at only 20 per
cent. of the normal requirements in the winter months, but was adequate
in the summer months. Yet with over 250 children there were but few
cases of gingivitis including only two of fusospirochaetal stomatitis
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H. H. STONES
observed during the three years commencing in 1942. Most observers
have been unable to establish any correlation between low plasma levels
of ascorbic acid and the more frequent type of gingivitis (Restarski and
Pijoan, 1944).
It may happen that a patient is suffering from a deficiency of more
than one of the vitamin components and in this case the clinical features
of the various deficiencies may occur together; as already mentioned
this particularly happens in connection with the vitamin B complex and
may also occur with vitamins B and C. Further, and particularly in
nutritionally neglected old and middle aged cases, there may be an
anaemia in which the blood picture shows a marked reduction both in
the haemoglobin and red cell count.
Hence these possibilities must be evaluated when instituting treatment
and any suspected deficiency including that of iron must be covered.
THE ORAL MANIFESTATIONS OF THE BLOOD DYSCRASIAS
In the blood dyscrasias a variety of oral manifestations may be
produced depending on the particular disease. As will be seen, in some
conditions they are but slight and in others severe. It is very important
for the dental practitioner to recognise the signs as he may be in a
position to be the first to examine a patient with a serious or fatal
disease, or sometimes if he operates without appreciating its significance,
the patient may be subjected to a dangerous risk. It is proposed to
mention representative types that illustrate the effect on the oral mucosa.
The aetiology and haematology are reviewed by Sturgis (1948) and
Whitby and Britton (1950).
Hypochromic Anaemia
Idiopathic hypochromic anaemia.-This usually occurs in young and
adult women and is caused by a deficient absorption of iron, which is
frequently associated with the hypochlorhydria that so often accompanies
the condition.
The blood picture usually shows that the red cell count is somewhat
reduced and red blood corpuscles are smaller than normal. The colour
index is low, being about 0 5 to 0 6 while the haemoglobin is reduced
to 40 per cent. or 50 per cent.
The oral mucosa is pale and there is a tendency to bleed from the
gingivae. The tongue is occasionally smooth due to atrophy of the
filiform papillae, and sometimes shows indentations from the teeth.
The general symptoms include pallor, breathlessness and palpitation.
There may be koilonychia, that is atrophic, thin and spoon-shaped nails.
The condition improves following the oral administration of iron
preparations.
Plummer-Vinson Syndrome.-This condition usually occurs in middle
aged females. It is associated with hypochromic anaemia and sometimes
with hypochlorhydria. There may be an associated vitamin B complex
deficiency.
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ORAL MANIFESTATIONS IN SYSTEMIC DISEASES
There are atrophic lesions of mucosal surfaces including the buccal
and pharyngeal mucosa. Dysphagia is a feature. The tongue is smooth
and sore, due to atrophy of the filiform papillae, and sometimes it is
wrinkled. The mouth may show angular lesions as occurs in riboflavin
deficiency.
There is paleness, weakness and sometimes koilonychia. Ahlbom
(1935) cotlsiders that this syndrome is responsible for a high proportion
of the buccal and pharyngeal cancer that occurs in women. Darby (1946)
emphasizes the importance of the iron deficiency and reports six
representative cases in which the oral condition remained after vitamin B
complex therapy but was alleviated with the administration of iron.
Pernicious Anaemia
This type of macrocytic anaemia has now been shown to be due to
a deficiency of an anti-anaemia substance. The latter is normally
provided through the interaction of the intrinsic factor of Castle which
is in the gastric secretion, with the extrinsic factor which is thought to be
a thermostable component of the vitamin B complex as yet unidentified.
Achlorhydria is a most constant finding.
Diagnosis is made from the blood picture. The red cell count is low,
even falling below 1 million per c.mm., and there is anisocytosis,
poikilocytosis and nucleated red cells. The colour index is high. There
is a leukopenia.
A characteristic early feature that occurs in about two-thirds of the
cases is recurrent soreness of the tongue. During an exacerbation the
tongue becomes very painful and red. The whole of the dorsum is
usually affected though it may be limited to certain areas. Sometimes
there is ulceration. In many cases, if untreated, there is eventually
atrophy of the filiform papillae and desquamation of epithelium so that
the tongue appears smooth-the typical Hunter's glossitis. It is nearly
always clean.
The lips and oral mucosa, including that of the palate, occasionally
have a pale yellowish appearance.
The skin sometimes has a pale yellowish tint. There are neurological
and gastro-intestinal symptoms.
With intramuscular injections of liver extract or vitamin B12 the oral
and general symptoms are alleviated.
Sprue
In this disease, a macrocytic hyperchromic anaemia and multiple
vitamin deficiencies may occur during its course. The cause is unknown
and it is noteworthy that though it is endemic in certain tropical regions
the natives are not usually affected, an exception to this being in Puerto
Rico. In recent years non-tropical sprue or idiopathic steatorrhoea has
been observed in more temperate climates.
The outstanding pathological feature is that the mucosa of the
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H. H. STONES
alimentary tract from the oral cavity to anus tends to undergo atrophic
changes, and the liver and pancreas may also atrophy. Hence
steatorrhoea is a feature of the disease. The bone marrow may show
aplastic or hyperplastic changes.
In view of the mucosal changes a multiple vitamin deficiency is to be
expected and Cayer, Ruffin and Perlzweig (1945) have shown that there
are low values for certain components of the vitamin B complex,
particularly thiamin and riboflavin, though the nicotinic acid level is not
much affected, and for vitamins A and C.
The oral lesions usually occur after the typical general symptoms.
The most noteworthy change is in the tongue which may show atrophy
of the papillae and desquamation of epithelium so that it becomes smooth,
red and sensitive. Only a part of the tongue may be affected either one
or both sides, or the tip or dorsum, thereby giving it a patchy appearance.
Occasionally the affected areas and also the buccal mucosa are covered
with patches of a yellowish grey membranous ulceration. Somewhat
rarely the tongue has a fissured appearance.
Lesions sometimes occur at the angles of the mouth.
The general symptoms vary, typical features being persistent diarrhoea
with frothy light coloured stools and weakness.
Purpura
Haemorrhages from mucous membranes and into the skin and joints
can be classified into symptomatic or non-thrombocytopenic purpura and
thrombocytopenic purpura.
Symptomatic or non-thrombocytopenic purpura.-In one type the
probable pathology is toxic damage to cells of the capillary walls allowing
the extravasation of red blood corpuscles. It is observed in various
infections, toxic disturbances, vitamin C and P deficiency, and in
hereditary familial purpura simplex.
Another type is due to a deficiency of the normal clotting elements of
the blood such as prothrombin, fibrinogen, vitamin K, or to qualitative
changes in the blood platelets.
Thrombocytopenic purpura.-In this condition there is a marked
reduction in the number of platelets in the blood from the normal
400,000 or 500,000 per cmm. to 60,000 per cmm. or even less. The
bleeding time is prolonged to several times the normal level of four
minutes, though the clotting time is unaffected. There is defective clot
retraction and a positive tourniquet test. Acute and chronic recurrent
forms are observed.
The oral manifestations of purpura are of varying severity. The
symptomatic type may only show petechiae and blebs containing blood
in the gingivae or other parts of the mucosa. In the severe and
haemorrhagic types the gingivae are swollen and purplish, and pressure
from dentures may even induce bleeding. There is bleeding from other
mucous membranes, and petechiae and ecchymoses occur on the skin.
The patient has the features arising from loss of blood.
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ORAL MANIFESTATIONS IN SYSTEMIC DISEASES
Extraction of teeth should be avoided in severe cases whenever possible.
but if essential a time should be chosen when there is remission of
symptoms, and suitable precautions should be taken.
Haemophilia
True haemophilia is a hereditary disease of a sex linked Mendelial
character, that is only transmitted through the female, though the
symptoms only occur in the male. It is considered to be due to a
deficiency of thromboplastinogen in the blood (Quick, 1947). The
coagulation time of the blood is greatly prolonged though the bleeding
time is not unduly affected. There is eventually normal clot retraction.
The tourniquet test is negative.
The gingivae and nasal mucosa are liable to haemorrhage. The
patient is very subject to ecchymoses; also haemorrhages occur into the
joints which become swollen and tender. There may be all the features
of anaemia.
Extraction of teeth must be avoided and only performed as a last
resort. In this case adequate precautions must be undertaken.
Agranulocytosis
The onset of this disease in a number of cases has been associated
with taking drugs of the amidopyrine series. It has also been reported
following the administration of the barbiturates, sulphonamides
(Marshall, 1950), neoarsphenamine (McGibbon and Glyn-Hughes, 1943),
gold preparations, and a case has occurred during penicillin therapy
(Spain and Clarke, 1946).
The blood picture shows a considerable reduction in the granulocytes;
the white count is low and the polymorphonuclears may be 5 per cent.
or under.
The oral lesions are a characteristic feature of the disease. The mucous
membranes of the fauces, the gingivae and buccal mucosa become swollen
and inflamed and may be covered with an exudate. Severe ulceration
may occur involving the fauces, posterior wall of the pharynx, soft and
hard palates, oral mucosa and gingivae. The organisms act rapidly
upon the tissues because of the lack of phagocytic granulocytes and the
lesions progress rapidly to necrosis.
The rectum and vagina may be similarly affected.
The onset is sudden and accompanied by a raised temperature. There
are severe constitutional symptoms and the mortality rate is from 50 per
cent. to 80 per cent.
Leukaemias
Under the term leukaemia is included a variety of conditions in which
the white blood corpuscles are affected, both in number and in form. The
cause is unknown.
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H. H. STONES
The leukaemias can be classified depending on whether the condition
is acute or chronic and on the type of cell involved; also there is the
aleukaemia phase to be considered. They all have a fatal termination.
(a) Acute leukaemia (myelogenous, lymphatic and monocytic types).
In acute leukaemia the total white count may not be high at the beginning
but is raised to an extent that may vary from 20,000 to upwards of
100,000 per cmm. in the terminal stages.
In the myelogenous type the predominant cells are the primitive
myeloblasts and myelocytes, these forming 80-90 per cent. of the count.
In the lymphatic type, lymphoblasts and lymphocytes similarly form
some 90 per cent. of the count.
In the monocytic type, the monocytes predominate.
There is usually a thrombocytopenia.
The disease most frequently occurs in childhood. The oral mucosa is
affected at an early stage. Frequently the gingivae are swollen and
tend to bleed. They become dark red in colour as the condition
progresses and there may be a tendency to slow but continuous
haemorrhage. Ulcerative lesions develop in the gingivae, palate and
fauces which become secondarily infected and rapidly progress to
gangrene.
Biopsy of the gums shows infiltration with the primitive cells. Burket
(1944) states that the extensive sloughing and occasionally observed
periapical abscess are due to thrombosis of the vessels supplying these
parts.
There are severe haemorrhages from other mucous membranes and
pyrexia and bleeding into the skin. As a result of the continuous
haemorrhages, signs of secondary anaemia develop with a low haemoglobin
and colour index. Eventually there are petechiae and ecchymoses
on the skin.
Neither the spleen nor lymph nodes are markedly enlarged in the acute
conditions. The termination is fatal in either several weeks or months.
Fitzgerald (1943) has reported nine cases and Matheson (1949) four
cases of leukaemia.
Two patients have come under observation who demonstrate the
importance of these diseases to the dental practitioner. The first is of
interest as the gingival condition has been the first symptom of acute
leukaemia. The patient, a female aged 16 years, attended because of
bleeding from the gums on the slightest provocation. There was a
history of haemorrhage following a previous tooth extraction. Examination
revealed swelling of the gingivae. The patient was pale, but stated
she felt well.
Blood examination showed an acute leukaemia with an almost daily
change from a monocytic to myelogenous type. The termination was
fatal in four weeks' time.
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ORAL MANIFESTATIONS IN SYSTEMIC DISEASES
The second patient was a male aged 16 years who developed acute
myelogenous leukaemia following tooth extraction, though there had
previously been no sign of the disease. There was marked enlargement
and ulceration of the gingivae with gangrene of the soft palate and fauces,
which sloughed away. There was a continuous and intractable oozing of
blood from the oral tissues. The blood picture was typical of
myelogenous leukaemia. The patient only survived for several weeks.
(b) Chronic leukaemia (myelogenous and lymphatic types).-In chronic
myelogenous leukaemia the white cell count shows an increase up to
200,000 or even to 500,000 per cmm. In the early stages adult
polymorphonuclears predominate though myeloblasts and myelocytes are
present.
In chronic lymphatic leukaemia the white cell count may reach 50,000
to 100,000 per cmm. of which some 90 per cent. are small lymphocytes
with occasional lymphoblasts.
In both types the primitive cells gradually increase until the blood,
after a varying period of time, presents the features of the acute type.
Chronic leukaemias frequently occur in middle age.
In both types the onset is gradual. Hypertrophic gingivitis occurs
but the gingival lesions are not so striking unless an acute stage develops
and then there is the tendency to the gingival features already described.
In chronic myelogenous leukaemia the characteristic feature is a
considerably enlarged spleen. In the lymphatic type there is enlargement
of the lymph nodes and the spleen is also sometimes increased in size.
(c) Aleukaemic leukaemia.-In this condition the total number of
white cells is low and sometimes may only reach 1,000 per cmm., but
immature cells are present which may be either of the myoblast,
lymphoblast or monoblast type. These cases develop into one of the
typical leukaemias described above.
A case with unilateral swelling and pain of the jaw and hypertrophic
gingivitis of the same side has been reported by Neger (1939).
Infectious Mononucleosis
In glandular fever there is a leucocytosis of 10,000 to 30,000 cells per
cmm. Lymphocytes, many of which show the morphology of
" monocytoid" cells, eventually form from 60 to 90 per cent. of the
total, though this may not be the case in the early stages.
It is characterized by respiratory symptoms and temperature. There
may be oedema and inflammation of the pharynx, soft palate and uvula,
and ulceration of the fauces. Ravenna and Snyder (1948) have reported
the oral mucosa as being sometimes inflamed though to a lesser extent,
together with the other features in a group of young adults. There is
enlargement of the lymph nodes, especially the cervical group.
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H. H. STONES
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